Topical formulations for delivery of hedgehog inhibitor compounds and use thereof

ABSTRACT

Compositions for topical administration of a hedgehog inhibitor compound are described. In one embodiment, the hedgehog inhibitor compound is patidegib and the topical composition comprises the compound in a solvent system of a monohydric primary alcohol and a polyol in a w/w ratio of between about 0.9-1.8. In another embodiment, the hedgehog inhibitor is itraconazole and the topical composition comprises the compound in a solvent system comprising a monohydric primary alcohol and an optionally lower alkyl end-capped oligomeric alkylene glycol in a w/w ratio of between about 0.8 and 2.6 and a fused bicyclic ether. Method of using the compositions are also described, where in one embodiment, the compositions are topically applied for treating or preventing basal cell carcinoma.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Non-Provisional patentapplication Ser. No. 16/239,457, filed Jan. 3, 2019, which is aDivisional of U.S. Non-Provisional patent application Ser. No.15/173,257, filed Jun. 3, 2016, now U.S. Pat. No. 10,369,147, Issue DateAug. 6, 2019, which claims the benefit of U.S. Provisional ApplicationNo. 62/171,117, filed Jun. 4, 2015, and of U.S. Provisional ApplicationNo. 62/275,185, filed Jan. 5, 2016. All aforementioned applications areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The subject matter described herein relates to compositions for topicalapplication of a hedgehog inhibitor compound and to topical deliverysystems for administration of a hedgehog inhibitor compound.

BACKGROUND

Drug administration by topical skin application of a drug offersdistinct advantages over conventional administration methods. Forexample, some drugs cannot be absorbed in the digestive tract andintravenous and subcutaneous administration by injection is inconvenientand invasive. Oral and intravenous administration for treatment of alocalized skin condition is undesirable as the drug is circulatedsystemically rather than restricted to the localized, diseased area.Yet, due to the protective nature of skin serving its intended functionof being resistant to external perturbations, only a limited number ofdrugs are bioavailable via topical application.

Drug administration via the skin may be transdermal or intradermal (alsoreferred to as local or dermal). Transdermal administration involvestransport through the skin such that a therapeutic amount of the drug isachieved in the systemic blood circulation. Intradermal or topicaladministration of a drug involves entry of the drug across the stratumcorneum for a cutaneous or local skin effect; that is thepharmacological effect of the drug is localized to the intracutaneousregions of drug penetration and deposition. Preferably, intradermalabsorption occurs with little or no systemic absorption or accumulation.Intradermal absorption of a drug involves partitioning of the drug fromthe applied vehicle into the stratum corneum; diffusion of the drugthrough the stratum corneum; and partitioning of the drug from thestratum corneum into the epidermis. In contrast, transdermal absorptionfurther involves diffusion of the drug through the epidermis; andcapillary uptake of the drug for circulation in the blood.

Whereas transdermal compositions are intended to deliver drugs forsystemic circulation, a different composition would be needed to deliverthe same drug intracutaneously. Topical formulations that achievedelivery of a drug across the stratum corneum and retention of themajority of the drug dermally such that it does not enter the bloodstream in significant amounts are complicated to design and requireinnovative approaches. Several factors determine the permeability of theskin or of specific layers, in particular the stratum corneum, of theskin to drug compounds. These factors include the characteristics of theskin, the characteristics of the drug compound (e.g., its size(molecular weight or molecular volume), itslipophilicity/hydrophilicity, its polarity), the dosage of the drugcompound applied, interactions between the drug compound and thedelivery vehicle, interactions between the drug compound and the skin,and interactions of the drug and the skin in the presence of theingredients in the delivery vehicle. As a result of the multitude offactors involved in administration of a drug intracutaneously, it isgenerally accepted that whether intracutaneous delivery of a drugcompound can be achieved in an amount sufficient for therapy isuncertain. Penetration enhancers are commonly used in transdermaldelivery to achieve penetration of a drug across the stratum corneumtypically to provide for systemic delivery of the drug, rather than itsretention in the epidermis or dermis. Thus, topical administration,while desired from a patient convenience and drug delivery view, hasbeen largely unsuccessful for many compounds as evidenced by therelatively few drugs approved for topical administration.

A condition that would benefit from a topical formulation that achievesintracutaneous delivery of a drug is basal cell carcinoma (BCC), themost common form of skin cancer in the United States. BCC is observed inthe general population typically on sun-exposed areas of the skin, andin subjects with the Basal Cell Nevus Syndrome, also known as Gorlinsyndrome, an inherited condition where the skin is prone to developingBCCs. Although BCCs rarely spread (i.e., metastasize) to other parts ofthe body, they can be destructive and disfiguring. A variety of surgicaland non-surgical therapies are available for BCCs. Nonsurgical therapiesinclude radiation therapy, chemotherapy, and immunotherapy. Thesetherapies can be useful for definitive treatment of primary tumors andsome recurrent BCC tumors and for relieving symptoms associated withinoperable tumors. However, some of these therapies also can havesignificant unpleasant side effects. Side effects of radiation therapyand certain chemotherapies are well documented. One form ofimmunotherapy involves intralesional injections of interferon. Whileinterferon therapy can be effective against BCC, the multipleintralesional injections can require several clinic visits per week formany weeks and are painful. Thus, there remains a need for anon-surgical therapy for BCC that offers better patient convenience.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

In one (or a first) aspect, a composition comprising a hedgehoginhibitor compound and a solvent system comprising (i) a monohydricprimary alcohol and a polyol in a w/w ratio of between about 0.9-1.8 and(ii) a buffer or a fatty acid comprising between 13-22 carbon atoms,wherein the hedgehog inhibitor compound is present in the solvent systembetween about 0.1-10 wt % is provided.

In another (or second) aspect, a composition is provided that iscomprised of a hedgehog inhibitor compound and a solvent system, thehedgehog inhibitor having a saturation solubility in the solvent systemof between about 0.1-10 wt %, preferably between about 2.5-8 wt %, andthe solvent system comprising between about 15-60 wt % of a monohydricprimary alcohol and between about 10-50 wt % propylene glycol.

Instill another (or third) aspect, a composition is provided that iscomprised of a hedgehog inhibitor compound and a solvent systemcomprising (i) a monohydric alcohol comprised of at least one of ethanoland benzyl alcohol and propylene glycol, the monohydric alcohol andpropylene glycol in a w/w ratio of between about 0.9-1.8 and (ii) abuffer or a fatty acid comprising between 13-22 carbon atoms, whereinthe hedgehog inhibitor compound is present in the solvent system betweenabout 0.1-10 wt %.

In one embodiment, the monohydric alcohol is of the form R—OH, where Ris selected from methyl, ethyl, propyl, butyl, and pentyl. In anotherembodiment, the monohydric alcohol is represented by the structureC_(n)H_(2n)—OH, where n is 1, 2, 3 or 4.

In yet another embodiment, the monohydric alcohol additionally includesbenzyl alcohol. In still another embodiment, the monohydric primaryalcohol is a combination of ethanol and benzyl alcohol. In anotherembodiment, the primary monohydric alcohol comprises phenoxyethanol.

In another embodiment, the solvent system further comprises diethyleneglycol monoethyl ether.

In another embodiment, the fatty acid is a saturated fatty acid. In oneembodiment, the saturated fatty acid is selected from myristic acid(C14), palmitic acid (C16), stearic acid (C18) and arachidic acid (C22).In yet another embodiment, the saturated fatty acid is iso-stearic acid.

In one embodiment, the hedgehog inhibitor compound is present in thesolvent system in an amount between about 2-8 wt %.

In one embodiment, the solvent system comprises between about 1-3 wt %benzyl alcohol. In still another embodiment, the solvent system furthercomprises diethylene glycol monoethyl ether. In yet another embodiment,the solvent system comprises diethylene glycol monoethyl ether and doesnot comprise benzyl alcohol.

In still another embodiment, the monohydric alcohol is ethanol and theratio (w/w) of ethanol to diethylene glycol monoethyl ether is withinabout 10-20% of the ratio (w/w) of ethanol to propylene glycol.

In another embodiment, the monohydric alcohol is ethanol and the ratio(w/w) of ethanol to diethylene glycol monoethyl ether is the same as theratio (w/w) of ethanol to propylene glycol.

In one embodiment, the solvent system comprises a buffer at pH 7.5.

In yet another embodiment, the composition further comprises a gellingagent. An exemplary gelling agent is, in one embodiment,hydroxypropylcellulose.

In one embodiment, the hedgehog inhibitor is patidegib or is acombination of patidegib and itraconazole. In another embodiment, thehedgehog inhibitor is itraconazole.

In another (or fourth) aspect, a composition is provided that iscomprised of patidegib and a solvent system comprising (i) ethanol andpropylene glycol in a w/w ratio of between about 0.9-1.8, (ii)diethylene glycol monoethyl ether, and (iii) a buffer, wherein thehedgehog inhibitor compound is present in the solvent system in anamount between about 0.1-10 wt %.

In one embodiment, the ratio (w/w) of ethanol to diethylene glycolmonoethyl ether is within about 10-20% of the ratio (w/w) of ethanol topropylene glycol. In another embodiment, the ratio (w/w) of ethanol todiethylene glycol monoethyl ether is the same as the ratio (w/w) ofethanol to propylene glycol.

In another (or fifth) aspect, a composition is provided that iscomprised of patidegib and a solvent system comprising (i) ethanol,benzyl alcohol and propylene glycol, the ethanol and benzyl alcohol in aw/w ratio with propylene glycol of between about 0.9-1.8 and (ii) afatty acid comprising between 13-22 carbon atoms, wherein the hedgehoginhibitor compound is present in the solvent system in an amount betweenabout 0.1-10 wt %.

In one embodiment, the fatty acid is a saturated fatty acid. In anotherembodiment, the saturated fatty acid is selected from myristic acid(C14), palmitic acid (C16), stearic acid (C18) and arachidic acid (C22).In still another embodiment, the saturated fatty acid is iso-stearicacid.

In one embodiment, the solvent system comprises between about 1-3 wt %benzyl alcohol.

In another (or sixth) aspect, a composition is provided that consistsessentially of patidegib and a solvent system comprising ethanol andpropylene glycol in a w/w ratio of between about 0.9-1.8, wherein thepatidegib has a saturation solubility in the solvent system of betweenabout 2.5-8 wt % and wherein formulation provides an in vitroconcentration of patidegib in the dermis of greater than about 250 μM 48hours after topical application.

In one embodiment, the solvent system further comprises diethyleneglycol monoethyl ether and a buffer.

In another embodiment, the solvent system further comprises a fatty acidcomprising between 13-22 carbon atoms.

In still another embodiment, the solvent system further comprises benzylalcohol.

In another (or seventh) aspect, a composition is provided that consistsessentially of patidegib and a solvent system consisting of ethanol andpropylene glycol in a w/w ratio of between about 0.9-1.8, diethyleneglycol monoethyl ether and a buffer.

In still another (or eighth) aspect, a composition is provided thatconsists essentially of patidegib and a solvent system consisting ofethanol and benzyl alcohol in a w/w ratio with propylene glycol ofbetween about 0.9-1.8 and a saturated fatty acid comprising between13-22 carbon atoms.

In yet another (or ninth) aspect, provide is a composition comprising ahedgehog inhibitor compound and a solvent system comprising (i) amonohydric primary alcohol and an optionally lower alkyl end-cappedoligomeric alkylene glycol in a w/w ratio of between about 0.8 and 2.6and (ii) a fused bicyclic ether having from 8-14 carbon atoms, whereinthe hedgehog inhibitor compound is present in the solvent system betweenabout 0.1-10 wt %.

In one or more embodiments related to the ninth aspect, the w/w ratio ofthe monohydric primary alcohol and the optionally lower alkyl end-cappedoligomeric alkylene glycol is between about 1.0 and 2.4, or is betweenabout 1.0 and 2.3. Exemplary monohydric alcohols have been previouslydescribed. For example, in one or more embodiments, the monohydricalcohol is of the form R—OH, where R is selected from methyl, ethyl,propyl, butyl, and pentyl. In one or more additional embodiments, themonohydric alcohol is represented by the structure C_(n)H_(2n)—OH, wheren is 1, 2, 3 or 4. In a preferred embodiment of the foregoing, R isethyl.

In one or more additional embodiments related to the ninth aspect, orits related embodiments, the monohydric primary alcohol comprises benzylalcohol. In one or more exemplary related embodiments, the monohydricprimary alcohol comprises a mixture of a C1-C6 primary aliphatic alcoholand benzyl alcohol. In one or more particular embodiments, thecomposition comprises ethyl alcohol and benzyl alcohol. In one or morerelated embodiments, the composition comprises from about 1% to about 8%by weight benzyl alcohol, or alternatively, comprises from about 2% toabout 6% by weight benzyl alcohol. In yet one or more additionalembodiments related to the ninth aspect, the w/w ratio of the monohydricalcohol to benzyl alcohol is in a range of about 3 to 11, or morepreferably, is in a range of about 4 to 10.

In one or more additional embodiments related to the ninth aspect, thepercent by weight of benzyl alcohol is less than the percent by weightof the optionally lower alkyl end-capped oligomeric alkylene glycol andis also less than the percent by weight of the fused bicylic etherhaving from 8-14 carbon atoms.

In one or more particular embodiments, the optionally lower alkylend-capped oligomeric alkylene glycol is end-capped. Illustrative endcapping groups include a methyl (—OCH₃) or an ethyl (—OCH₂CH₃) group.

In one or more embodiments, the optionally lower alkyl end-cappedoligomeric alkylene glycol comprises from 2 to 4 ethylene oxide repeatunits. In one or more particular embodiments, the optionally lower alkylend-capped oligomeric alkylene glycol comprises 2 ethylene oxide repeatunits. In yet a further embodiment, the optionally lower alkylend-capped oligomeric alkylene glycol is end-capped and is diethyleneglycol monoethyl ether (DEGMEE).

In one or more further embodiments, e.g., related to the ninth aspect,the optionally lower alkyl end-capped oligomeric alkylene glycol is anon-end capped oligomeric ethylene glycol having a number averagemolecular weight from 300-600 (i.e., a PEG having an average molecularweight between about 300 and 600. In one or more particular embodiments,the non-end capped oligomeric ethylene glycol has a number averagemolecular weight of 400.

In one or more particular embodiments, the optionally lower alkylend-capped oligomeric alkylene glycol is either diethylene glycolmonoethyl ether or is PEG (e.g., PEG 300-600). In yet a furtherembodiment, the composition comprises either diethylene glycol monoethylether or PEG (e.g., PEG 300-600) but does not comprise both.

In one or more further embodiments related to the ninth aspect (and itsrelated embodiments), the w/w ratio of the optionally lower alkylend-capped oligomeric alkylene glycol to the fused bicyclic ether havingfrom 8-14 carbon atoms is in a range between about 1 and 2, oralternatively, is in a range between about 1.2 and 1.8.

In one or more specific embodiments, the w/w ratio of the optionallylower alkyl end-capped oligomeric alkylene glycol to the fused bicyclicether having from 8-14 carbon atoms is about 1.7.

In one or more further embodiments related to the ninth aspect, thecombined percent by weight of the optionally lower alkyl end-cappedoligomeric alkylene glycol and the fused bicyclic ether having from 8-14carbon atoms is from 30-50 w/w %.

In yet an additional one or more embodiments, the combined percent byweight of the optionally lower alkyl end-capped oligomeric alkyleneglycol and the fused bicyclic ether having from 8-14 carbon atoms is 40w/w %.

In one or more particular embodiments, the fused bicyclic ether havingfrom 8-14 carbon atoms comprises two fused tetrahydrofuran rings. In yetone or more additional embodiments, the two fused tetrahydrofuran ringspossess two methoxy substituents. In a preferred embodiment, the fusedbicyclic ether is dimethyl isosorbide.

In yet another embodiment related to the ninth aspect or its relatedembodiments, the composition is absent benzyl alcohol. In yet anadditional one or more further related embodiments, the composition isabsent benzyl alcohol and further comprises phenoxyethanol, e.g., from0.5 to 2.5 weight percent phenoxyethanol. In yet a further embodimentrelated to the foregoing, the composition is absent both benzyl alcoholand propylene carbonate, yet comprises phenoxyethanol.

In one or more additional embodiments related to at least the ninthaspect, the composition further comprising from 1 to 7 weight percentpropylene carbonate.

In one or more preferred embodiments, the composition comprises anN-methyl lactam.

In one or more particular embodiments, the composition comprisesN-methyl pyrrolidone. In one or more embodiments related to theforegoing, the composition comprises N-methyl pyrrolidone, and the w/wratio of the monohydric primary alcohol and the optionally lower alkylend-capped oligomeric alkylene glycol is between about 1.0 and 1.5. Inyet one or more further embodiments, the percentage by weight of each ofthe monohydric primary alcohol, the optionally lower alkyl end-cappedoligomeric alkylene glycol, and N-methyl pyrrolidone is from 20-30. In apreferred embodiment, the composition comprises ethanol, diethyleneglycol monoethyl ether, and N-methyl pyrrolidone.

In yet an additional aspect (or tenth aspect), provided is a compositioncomprising a hedgehog inhibitor compound and a solvent system comprising(i) a ternary combination of low molecular weight aliphatic polyols(e.g., having molecular weights in a range from 50 to 550) having 2 or 3hydroxyl groups and a lower alkyl end-capped oligomeric alkylene glycolin a w/w ratio of between about 1.5 and 2.4 and (ii) a fused bicyclicether having from 8-14 carbon atoms, wherein the hedgehog inhibitorcompound is present in the solvent system between about 0.1-10 wt %.

In one or more embodiments related to the tenth aspect, the ternarycombination of low molecular weight aliphatic polyols comprisesHOCH₂C(OH)HR′ where R′ is —CH₃ or —CH₂OH. In yet a more particularembodiment, the ternary combination of low molecular weight aliphaticpolyols comprises glycerol and propylene glycol.

In one or more further embodiments, the ternary combination of lowmolecular weight aliphatic polyols comprises glycerol, propylene glycoland polyethylene glycol. In one or more further embodiments, thepolyethylene glycol has a number average molecular weight from 300-500.In one or more particular embodiments, the w/w ratio of propylene glycolto glycerol is between 1.5 and 2.5 and the w/w ratio of polyethyleneglycol to glycerol is between 1.5 and 2.5.

In one or more further embodiments related to the tenth aspect, the w/wratio of the ternary combination of aliphatic polyols to the lower alkylend-capped oligomeric alkylene glycol is in a range from 1.8 to 2.1. Inyet one or more further embodiments, the composition comprises fromabout 40 to 55 percent by weight of the ternary combination of aliphaticpolyols.

In yet another embodiment related to the tenth aspect, the compositionis absent an aliphatic monohydric alcohol (e.g., ethanol).

In one or more additional embodiments related to the tenth aspect, thecomposition further comprises from about 1% to about 8%, or from about2% to about 6% by weight benzyl alcohol.

In one or more additional embodiments related to the tenth aspect, theweight percent of benzyl alcohol is less than the weight percent of thelower alkyl end-capped oligomeric alkylene glycol and is also less thanthe weight percent of the fused bicylic ether having from 8-14 carbonatoms.

In one or more further embodiments, the lower alkyl end-cappedoligomeric alkylene glycol is end-capped with a methyl or an ethylgroup. In one or more particular embodiments, the lower alkyl end-cappedoligomeric alkylene glycol comprises 2 ethylene oxide repeat units. In apreferred embodiment, the lower alkyl end-capped oligomeric alkyleneglycol is diethylene glycol monoethyl ether (DEGMEE).

In one or more further embodiments directed to at least the tenthaspect, the w/w ratio of the lower alkyl end-capped oligomeric alkyleneglycol to the fused bicyclic ether having from 8-14 carbon atoms is in arange between about 1 and 2, or is more preferably in a range betweenabout 1.2 and 1.8.

In one or more additional embodiments related to at least the tenthaspect, the w/w ratio of the lower alkyl end-capped oligomeric alkyleneglycol to the fused bicyclic ether having from 8-14 carbon atoms isabout 1.7.

In one or more further embodiments related to the tenth aspect, thecombined percent by weight of the lower alkyl end-capped oligomericalkylene glycol and the fused bicyclic ether having from 8-14 carbonatoms is from 30-50 w/w %. In a particular embodiment, the combinedpercent by weight of the lower alkyl end-capped oligomeric alkyleneglycol and the fused bicyclic ether having from 8-14 carbon atoms is 40w/w %.

In one or more particular embodiments related to the tenth (or ninth)aspect, the fused bicyclic ether having from 8-14 carbon atoms isdimethyl isosorbide.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is absent a surfactant.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is non-aqueous.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is absent a triglyceride.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is absent a complexing agent such as a cyclodextrin.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is not an oil-in-water emulsion.

In one or more embodiments related to the ninth or tenth aspects, thecomposition is absent a hydrophobic oil.

In one or more additional embodiments related to the ninth or tenthaspects, the composition is absent a surfactant, is absent atriglyceride, is absent a complexing agent, is absent a hydrophobic oil,and is not an oil-in-water emulsion.

In yet a further embodiment related to the ninth or tenth aspects, thecomposition further comprising a gelling agent. In one or moreembodiments, the gelling agent is hydroxypropylcellulose. In one or morerelated embodiments, the composition is in the form of a gel.

In one or more further embodiments related to at least the ninth andtenth aspects, the hedgehog inhibitor compound is atriazolyl-triazolone. In one or more particular embodiments, thehedgehog inhibitor compound is itraconazole or is a combination ofitraconazole and patidegib.

In one or more additional embodiments related to the foregoing, thecomposition possesses a saturated solubility of itraconazole of fromabout 0.14-1.5 w/w percent, or more preferably, from about 0.25-1.0 w/wpercent.

In one or more further embodiments, the itraconazole is present in thesolvent system between about 0.1-5 wt %, or more preferably, is presentin the solvent system between about 0.1-2 wt %.

In yet another aspect, topical delivery system is provided that iscomprised of a composition as described herein. The topical deliverysystem can further comprise, in one embodiment, a backing member andmembrane joined to define a reservoir in which the composition iscontained. In one embodiment, the membrane is a non-rate controllingmembrane.

In another aspect, the present invention provides a method of treating askin cancer in a subject, the method comprising the topicaladministration to the skin of a subject a therapeutically effectiveamount of a composition comprising, consisting essentially of, orconsisting of a composition or topical delivery system as describedherein.

In still another aspect, a method for treating basal cell carcinoma isprovided, where the method comprises providing a composition asdescribed herein or a topical delivery system as described herein,whereby the providing comprises instructions to topically apply thecomposition of the system and wherein said topically applying achievesintracutaneous delivery of the hedgehog inhibitor compound in an amountsufficient for treating basal cell carcinoma, with a non-therapeuticconcentration of the compound present in the blood of the subject.

In still another aspect, a method for treating basal cell carcinoma isprovided, where the method comprises topically applying a composition asdescribed herein or a topical delivery system as described herein to asubject in need thereof, whereby the topically applying achievesintracutaneous delivery of the hedgehog inhibitor compound in an amountsufficient for treating basal cell carcinoma, with a non-therapeuticconcentration of the compound present in the blood of the subject.

In still another aspect, a method for preventing basal cell carcinoma ina subject at risk thereof is provided, where the method comprisestopically applying a composition as described herein or a topicaldelivery system as described herein to a subject in need thereof,whereby the topically applying achieves intracutaneous delivery of thehedgehog inhibitor compound in an amount sufficient for treating basalcell carcinoma, with a non-therapeutic concentration of the compoundpresent in the blood of the subject.

In yet another aspect, a method for slowing progression (i.e.,controlling the growth) of basal cell carcinoma in a subject with basalcell carcinoma or at risk of basal cell carcinoma is provided, where themethod comprises topically applying a composition as described herein ora topical delivery system as described herein to a subject in needthereof, whereby the topically applying achieves intracutaneous deliveryof the hedgehog inhibitor compound in an amount sufficient forcontrolling the growth of the basal cell carcinoma, with anon-therapeutic concentration of the compound present in the blood ofthe subject.

In one embodiment, the subject has Gorlin syndrome.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent by reference to thedrawings and by study of the following descriptions.

Additional embodiments of the present methods and compositions, and thelike, will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph showing the cumulative amount of patidegib permeatedacross human skin in vitro, in ng/cm², as a function of time, in hours,for five exemplary topical compositions of patidegib;

FIG. 1B is a bar graph showing the amount of patidegib, in ng, atvarious locations in a skin sample after 48 hours of in vitro contactwith five exemplary compositions of patidegib in a solvent system, wherethe bars correspond to amount of patidegib in the stratum corneum(dashes), epidermis (horizontal fill), dermis (diagonal fill) andreceiver fluid (dots);

FIG. 2A is a graph showing the cumulative amount of patidegib permeatedacross human skin in vitro, in ng/cm², as a function of time, in hours,for six exemplary compositions of patidegib in a solvent system;

FIG. 2B is a bar graph showing the amount of patidegib, in ng, atvarious locations in a skin sample after 48 hours of in vitro contactwith six exemplary compositions of patidegib in a solvent system, wherethe bars correspond to amount of patidegib in the stratum corneum(dashes), epidermis (horizontal fill), dermis (diagonal fill) andreceiver fluid (dots);

FIG. 3A is a graph showing the cumulative amount of patidegib permeatedacross human skin in vitro, in ng/cm², as a function of time, in hours,for six exemplary compositions of patidegib in a solvent system; and

FIG. 3B is a bar graph showing the amount of patidegib, in ng, atvarious locations in a skin sample after 48 hours of in vitro contactwith six exemplary compositions of patidegib in a solvent system, wherethe bars correspond to amount of patidegib in the stratum corneum(dashes), epidermis (horizontal fill), dermis (diagonal fill) andreceiver fluid (dots).

FIG. 4 is a graph demonstrating the cumulative amount of itraconazolepermeated through human skin per unit area (ng/cm²) over a 48 hour timeperiod when evaluated at each of the following time points (hours): 0,14, 18, 24, 26, 36, 40, 44 and 48 for representative topicalformulations comprising itraconazole as described in Example 9.

FIG. 5 is a bar graph illustrating the amount of itraconazole recovered(in ng) from each skin layer after the final 48 hour time point for eachof the representative formulations evaluated following apermeation/penetration experiment as described in detail in Example 9.For each test item (itraconazole formulation), data is provided fromleft to right along the horizontal axis for the stratum corneum,epidermis, dermis, and receiver fluid.

FIGS. 6A-6B are mean concentration-time profiles of patidegib (FIG. 6A)and its metabolite, IPI-230 (FIG. 6B) in Gottingen Minipig® plasma forthe test groups (male and female results combined) treated with 40mg/kg/day (closed circles) and 80 mg/kg/day (inverted diamonds)patidegib topically.

FIGS. 7A-7B are dose normalized C_(max) and AUC₀₋₂₄ relationships,respectively, of patidegib in Gottingen Minipig® plasma for the testgroups (male and female results combined) treated with 40 mg/kg/day and80 mg/kg/day patidegib topically, on Day 1 (closed circles), Day 14(inverted triangles) and Day 90 (closed squares) of the study (Example11).

DETAILED DESCRIPTION I. Definitions

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a “polymer” includes a single polymer aswell as two or more of the same or different polymers, reference to an“excipient” includes a single excipient as well as two or more of thesame or different excipients, and the like.

The compositions of the present disclosure can comprise, consistessentially of, or consist of, the components disclosed.

All percentages, parts and ratios are based upon the total weight of thetopical compositions and all measurements made are at about 25° C.,unless otherwise specified.

For any particular compound disclosed herein, any general or specificstructure presented also encompasses all conformational isomers,regioisomers, and stereoisomers that can arise from a particular set ofsubstituents, unless stated otherwise. Similarly, unless statedotherwise, the general or specific structure also encompasses allenantiomers, diastereomers, and other optical isomers whether inenantiomeric or racemic forms, as well as mixtures of stereoisomers, aswould be recognized by a skilled artisan.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, salts, compositions, dosage forms, etc., whichare—within the scope of sound medical judgment—suitable for use incontact with the tissues of human beings and/or other mammals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. In someaspects, “pharmaceutically acceptable” means approved by a regulatoryagency of the federal or a state government, or listed in the U.S.Pharmacopeia or other generally recognized pharmacopeia for use inmammals (e.g., animals), and more particularly, in humans.

The term “treating” is used herein, for instance, in reference tomethods of treating cancer, and includes the administration of acompound or composition or topical delivery system which reduces thefrequency of, or delays the onset of, symptoms of a medical condition(e.g., cancer) in a subject relative to a subject not receiving thecompound or composition or topical delivery system. This can includereversing, reducing, or arresting the symptoms, clinical signs, andunderlying pathology of the condition in a manner to improve orstabilize a subject's condition (e.g., regression of tumor growth).Treatment of basal cell carcinoma encompasses, for example, chronicmanagement of the condition, such as controlling the growth of the basalcell carcinoma, reducing the tumor burden, as well as prevention.

The terms “inhibiting” or “reducing” are used in reference to methods toinhibit or to reduce tumor growth (e.g., decrease the size of a tumor)in a population as compared to a untreated control population.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 95% or greater, of a given quantity.

“Oligomer” or “oligomeric” as used herein refers to a chemical entityhaving from 2 to 13 repeat units. For example, an oligomeric alkyleneglycol is having from 2 to about 13 alkylene glycol repeat units, suchas ethylene oxide or propylene oxide repeat units.

The term “end-capped” as used herein refers to a terminal or endpoint ofan entity such as an oligomer having ethylene oxide repeat units inwhich one of the terminal hydroxyl groups has been converted to anon-reactive group, such as an ether (—OR). Typically, although notnecessarily, the end-capping moiety is a lower alkoxy group, such as aC₁₋₆ alkoxy group. Examples of end-capping moieties include methoxy,ethoxy, propoxy, butoxy, and the like.

“Lower alkyl” refers to an alkyl group containing from 1 to 6 carbonatoms, and may be straight chain or branched, as exemplified by methyl,ethyl, n-butyl, i-butyl, t-butyl.

A “fused bicyclic ether” refers to a fused bicyclic ring system (i.e.,containing two fused aliphatic rings) comprising from 1 to 3 oxygenatoms (e.g., 1, 2 or 3) in the ring system. The fused bicyclic etherpossesses no unsaturation, and may comprise from 1 to 4 additionalsubstituents comprising atoms selected from carbon, hydrogen and oxygen.One example of a fused bicyclic ether is isosorbide dimethyl ether(synonyms include dimethyl isosorbide and1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitol), which possesses twomethoxy groups substituted on the dianhydro-D-glucitol ring system. Afused bicyclic ether having from “8-14 carbon atoms” refers to the totalnumber of carbon atoms contained in the fused bicyclic ether includingany substituents.

“Alkoxy” refers to an —O—R group, wherein R is alkyl, preferably C₁-C₆alkyl (e.g., methoxy, ethoxy, propoxy, etc.).

A “non-aqueous” formulation generally refers to a formulation comprisesless than 2% by weight water. Thus, a non-aqueous formulation maycomprise trace amounts of water, however water is not added as aformulation component.

A hydrophobic oil as used herein refers to a higher fatty acid ester,oils and fats, higher fatty acids, and higher acids, where higher refersto a carbon chain of 12-28 carbon atoms.

A low molecular weight polyol refers to a polyol having a molecularweight in a range from 50 to 550. For an oligomeric polyol such asoligomeric PEG, the molecular weight is generally a number averagemolecular weight.

“Optional” or “optionally” means that the subsequently describedcircumstance may but need not necessarily occur, so that the descriptionincludes instances where the circumstance occurs and instances where itdoes not.

By reserving the right to proviso out or exclude any individual membersof any such group, including any sub-ranges or combinations ofsub-ranges within the group, that can be claimed according to a range orin any similar manner, less than the full measure of this disclosure canbe claimed for any reason. Further, by reserving the right to provisoout or exclude any individual substituents, analogs, compounds, ligands,structures, or groups thereof, or any members of a claimed group, lessthan the full measure of this disclosure can be claimed for any reason.

All publications cited herein are hereby incorporated by reference intheir entirety.

II. Topical Formulations

A topical composition for intracutaneous delivery of a hedgehoginhibitor compound is described. Hedgehog inhibitor compounds andsolvent systems that together comprise the topical formulations will nowbe described.

A. Hedgehog Inhibitor Compounds

The Hedgehog polypeptide is a secreted protein that functions as asignaling ligand in the hedgehog pathway. Three different forms of thehedgehog protein are found in humans: Sonic hedgehog, Desert hedgehogand Indian hedgehog. Sonic hedgehog is the most prevalent hedgehogmember in mammals and also is the best characterized ligand of thehedgehog family. Prior to secretion, Sonic hedgehog undergoes anintramolecular cleavage and lipid modification reaction. The lipidmodified peptide is responsible for signaling activities. Inhibition ofthe hedgehog pathway in certain cancers has been shown to result ininhibition of tumor growth (Von Hoff D. et al., N. Engl. J. Med.,361(12):1164-72 (2009); Kim et al., Cancer Cell, 23(1):23-34 (2013)).Small molecule inhibition of hedgehog pathway activity results in celldeath in a number of cancer types (Tang, et al., N. Eng. J. Med., 366(23): 2180-2188 (2012); Kim, et al., J. of Clin. Oncol., 32: 1-7 (2014).

Hedgehog inhibitor compounds contemplated for use include, for example,those described and disclosed in U.S. Pat. Nos. 7,230,004, 7,812,164;8,669,365, U.S. Patent Application Publication No. 2008/0287420, U.S.Patent Application Publication No. 2008/0293755 and U.S. PatentApplication Publication No. 2013/0109700, the entire disclosures ofwhich are incorporated by reference herein. Examples of other suitablehedgehog inhibitors include those described in U.S. Patent ApplicationPublication Nos. US 2002/0006931, US 2007/0021493 and US 2007/0060546,and International Application Publication Nos. WO 2001/19800, WO2001/26644, WO 2001/27135, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354.

Additional examples of hedgehog inhibitors include, but are not limitedto, GDC-0449 (also known as RG3616 or vismodegib) described in, e.g.,Von Hoff D. et al., Engl. J. Med. 361(12):1164-72 (2009); Robarge K. D.et al., Bloorg Med Chem Lett., 19(19):5576-81 (2009); Rudin, C. et al.,New England J. ofMedicine, 361-366 (2009); BMS-833923 (also known asXL139) described in, e.g., in Siu, L. et al., J. Clin. Oncol. 2:15s(suppl; abstr 2501) (2010); LDE-225 described, e.g., in Pan S. et al.,ACS Med. Chem. Lett. 1(3): 130-134 (2010); LEQ-506 described, e.g., inNational Institute of Health Clinical Trial Identifier No. NCT01106508;PF-04449913 described, e.g., in National Institute of Health ClinicalTrial Identifier No. NCT00953758; hedgehog pathway antagonists disclosedin U.S. Patent Application Publication No. 2010/0286114; SMOi2-17described, e.g., U.S. Patent Application Publication No. 2010/0093625;SANT-1 and SANT-2 described, e.g., in Rominger C. M. et al., J.Pharmacol. Exp. Ther., 329(3):995-1005 (2009);1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett., 20(12):3618-22 (2010).

In certain embodiments, the hedgehog inhibitor is a steroidal alkaloidof the cyclopamine family.

In certain embodiments, the hedgehog inhibitor is a compound of formula(I):

or a pharmaceutically acceptable form thereof (e.g., a salt and/orsolvate) thereof; wherein:

R¹ is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R⁵,—N(R⁵)C(O)R⁵, or a sugar;

R² is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, orheterocycloalkyl;

or R¹ and R² taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR₂), or═C(R)₂;

R³ is H, alkyl, alkenyl, or alkynyl;

R⁴ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR, —C(O)R⁵, —CO₂R⁵,—SO₂R⁵, —C(O)N(R⁵)(R⁵), [C(R)₂]_(g)—R⁵, —[(W)—N(R)C(O)]_(g)R⁵,—[(W)—C(O)]_(g)R⁵, —[(W)—C(O)O]_(g)R⁵, —[(W)—OC(O)]_(q)R⁵,—[(W)—SO₂]_(g)R⁵, —[(W)—N(R⁵)SO₂]_(q)R⁵, —[(W)—C(O)N(R)]_(q)R⁵,—[(W)—O]_(q)R⁵, —[(W)—N(R)]_(q)R⁵, —W—NR₃ ⁺X⁻ or —[(W)—S]_(q)R⁵; whereineach W is independently for each occurrence a diradical such as analkylene; each q is independently for each occurrence 1, 2, 3, 4, 5, or6; and X⁻ is an anion (e.g., a halide);

each R⁵ is independently for each occurrence H, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkylor [C(R)₂]_(p)—R⁶; wherein p is 0-6; or any two occurrences of R⁵ on thesame substituent can be taken together to form a 4-8 membered optionallysubstituted ring which contains 0-3 heteroatoms selected from N, O S,and P; and

each R⁶ is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO₂(R),—C(O)N(R)₂, —OC(O)N(R)(R), —SO₂N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R),—OS(O)₂OR, —S(O)₂OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR);and

each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl oraralkyl; provided that when R², R³ are H and R⁴ is hydroxyl; R¹ cannotbe hydroxyl; provided that when R², R³, and R⁴ are H; R¹ cannot behydroxyl; and provided that when R², R³, and R⁴ are H; R¹ cannot besugar.

In certain embodiments, R¹ is H, hydroxyl, alkoxyl, aryloxy, or amino.

In some embodiments, R¹ and R² taken together along with the carbon towhich they are bonded, form ═O, ═N(OR), or ═S.

In other embodiments, R³ is H and/or R⁴ is H, alkyl, hydroxyl, aralkyl,[C(R)₂]_(q)—R⁵, [(W)—N(R)C(O)]_(q)R⁵, —[(W)—N(R)SO₂]_(q)R⁵,—[(W)—C(O)N(R)]_(q)R⁵, —[(W)—O]_(q)R⁵, —[(W)—C(O)]_(q)R⁵, or—[(W)—C(O)O]_(q)R⁵.

In yet other embodiments, R¹ is H or —OR, R² is H or alkyl, and R⁴ is H.

In yet other embodiments, R² is H or alkyl, R³ is H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; and/or R⁴ is H,alkyl, aralkyl, —[(W)—N(R)C(O)]_(q)R⁵, —[(W)—N(R)SO₂]_(q)R⁵,—[(W)—C(O)N(R)]_(q)R⁵, —[(W)—O]_(q)R⁵, —[(W)—C(O)]_(q)R⁵, or —[(W)C(O)O]_(q)R⁵.

In yet other embodiments, R¹ is sulfonamido.

Specific examples of hedgehog inhibitors include compounds, orpharmaceutically acceptable salts and/or solvates thereof, described inU.S. Pat. No. 7,812,164, incorporated by reference herein. Anillustrative example of a hedgehog inhibitor is the following compound,referred to herein as patidegib, previously referred to as “saridegib”and also known in the art as IPI-926:

The hedgehog inhibitor compounds described herein can be employed in apharmaceutically acceptable salt form, and in one embodiment, the saltform is the hydrochloride salt of Compound II, identified below asCompound II-a:

In certain other embodiments, the hedgehog inhibitor is atriazolyl-triazolone compound according to formula (or compound) III:

where R₁ is one or more independently selected halo groups substitutedon the phenyl ring (i.e., the phenyl ring may comprise 1, 2, 3, 4 or 5R₁ groups, that may be the same or different, where each R₁ is a halogroup). In some embodiments, the halo group is selected from chloro,bromo and fluoro. In one or more embodiments, the phenyl ring comprisesa single R₁ group that is ortho, meta or para to the attachment to thedioxolane or the dioxane moiety. In yet other embodiments, the phenylring comprises two R₁ groups that may be positioned in any configurationon the phenyl ring. In a preferred embodiment, the R₁ groups are thesame. In further embodiments, the phenyl ring comprises three R₁ groups,or even four R₁ groups, or even five R₁ groups. In some embodiments, theR₁ groups are the same. Further in reference to Compound III, n is 0 or1; that is to say, the oxygen containing heterocycle is either dioxaneor is dioxolane. In one preferred embodiment, n is 0. The substituentattached to the triazolone ring, R₂, is typically a branched or linearlower alkyl group; examples include but are not limited to methyl,ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

In some embodiments of Compound (III), n is 0 and R₁ represents twochloro groups. In some embodiments, R₁ represents two chloro groups thatare positioned ortho- and para- to the bond connecting the phenyl groupto a 1,3-dioxolane ring. In some embodiments of Compound (III), R₂ is—CCH₃CH₂CH₃. In certain other preferred embodiments, Compound III isitraconazole (Compound III-a,(2R,4S)-rel-1-(butan-2-yl)-4-{4-[4-(4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one)).Itraconazole possesses three chiral centers, and maybe used in theinstant topical formulations as a mixture of racemates, or in opticallypure form (i.e., of any one particular stereoisomer), or as a mixtureenriched in one or more of the stereoisomers. Itraconazole may also bein the form of a pharmaceutically acceptable salt. The commerciallyavailable drug (marketed as an antifungal) is provided as astereoisomeric mixture of four stereoisomers, i.e., a mixture of tworacemates, all of the stereoisomers having a cis configuration (wherethe hydrogen and the 2,4-dichlorophenyl group at the two chiral centersare on the same side of the dioxolane ring). Shi et al., ACS Med. Chem.Lett., 2010, 1, 155-159. In one or more embodiments, a composition ordelivery system comprises itraconazole as a stereoisomeric mixture offour stereoisomers, i.e., a mixture of two racemates, all of thestereoisomers having a cis configuration.

Itraconazole is a potent antagonist of the Hedgehog (Hh) signalingpathway that acts by a mechanism distinct from its inhibitory effect onfungal sterol biosynthesis. Itraconazole appears to act on the essentialHh pathway component Smoothened (Smo) by a mechanism distinct from thatof cyclopamine and other known Smo antagonists, and prevents the ciliaryaccumulation of Smo normally caused by Hh stimulation (Kim, J., et al.,Cancer Cell., 2010 Apr. 13; 17(4): 388-399).

B. Exemplary Solvent Systems and Compositions Comprising the SolventSystems

Solvent systems for topical administration of a hedgehog inhibitorcompound having a structure exemplified by Compound I or Compound IIIare described. As an exemplary compound in the solvent systems, a saltform of Compound II (patidegib), the hydrochloride salt form shown asCompound II-a, was used in some of the studies. Additional studies inwhich another exemplary compound, itraconazole, was used, are alsodescribed below (and in the examples which follow).

In a study detailed in Example 1, five topical formulations wereprepared. Ingredients in the compositions are summarized in Table 1 andin the tables presented in Example 1.

TABLE 1 Exemplary Topical Compositions Ethanol/ PG¹ benzyl isostearicphenoxy buffer³ Name Ratio DEGEE² alcohol acid ethanol (pH 7.5) HPCpatidegib SS5 1.00 18.7 1.9 — — 35.6 2.0 4.4 SS6 1.50 18.4 1.8 — — 25.72.0 6.2 SS14 1.25 18.8 — — 0.9 31.0 2.0 5.0 SS20 1.25 — 1.9 — — 49.5 2.03.7 SS22 1.56 — 1.9 14.2 — — 2.0 4.4 ¹PG = propylene glycol ²DEGEE =diethylene glycol monoethyl ether ³buffer pH 7.5 comprised of boric acid(0.16< adjusted with sodium hydroxide (0.1M)

The solvent system in one embodiment comprises a binary solvent systemof a monohydric alcohol having between about 1-6 carbon atoms and apolyol. In one embodiment, the monohydric alcohol is a primary alcoholselected from methanol, ethanol, 1-propanol, butanol, amyl alcohol(pentanol) and cetyl alcohol (hexadecane-1-ol). In another embodimentthe monohydric alcohol is a secondary alcohol such as isopropyl alcohol,and in another embodiment the monohydric alcohol is an aliphaticsecondary alcohol, e.g., a secondary alcohol lacking a ring structure.In yet another embodiment, the monohydric alcohol is one having 2-4 or2-3 carbon atoms, and in another embodiment it is a diol with 2-4 or 2-3carbon atoms. In one embodiment the polyol is a diol selected fromethylene glycol, propylene glycol, and 1,4-butanediol. The ratio of themonohydric alcohol to polyol is between about 0.9-1.8 or 0.9-1.7,preferably between about 0.95-1.60 or between about 1.0-1.56.

The solvent system in another embodiment is a ternary solvent systemcomprised of the monohydric alcohol and the polyol described above inthe binary solvent system and diethylene glycol monoethyl ether (DEGEE),benzyl alcohol, or both. In this ternary system, the monohydric alcoholto polyol is between about 0.9-1.8 or about 0.9-1.7, preferably betweenabout 0.95-1.60 or between about 1.0-1.56. When the third component isDEGEE, the ratio (w/w) of monohydric alcohol to DEGEE is within about10-20% of the ratio (w/w) of monohydric alcohol to polyol (or diol). Inanother embodiment, when the third component is DEGEE, the ratio (w/w)of monohydric alcohol to DEGEE is the same as the ratio (w/w) ofmonohydric alcohol to polyol (or diol).

The solvent system in another embodiment is a quaternary solvent systemcomprised of a monohydric alcohol monohydric alcohol having betweenabout 1-6 carbon atoms and a polyol, as described above in the binarysolvent system, and diethylene glycol monoethyl ether (DEGEE), benzylalcohol, or both, and as the fourth component, phenoxyethanol. In thisquaternary solvent system, the monohydric alcohol to polyol is betweenabout 0.9-1.8 or about 0.9-1.7, preferably between about 0.95-1.60 orbetween about 1.0-1.56. When the third component is DEGEE, the ratio(w/w) of monohydric alcohol having between about 1-6 carbon atoms toDEGEE is within about 10-20% of the ratio (w/w) of monohydric alcohol topolyol (or diol). In another embodiment, when the third component isDEGEE, the ratio (w/w) of monohydric alcohol to DEGEE is the same as theratio (w/w) of monohydric alcohol to polyol (or diol). Thephenoxyethanol is present in the system in an amount between about0.01-3 wt % or between about 0.07-2 wt %.

In another embodiment, the solvent system is a quaternary solvent systemcomprised of (i) a monohydric alcohol having between 1-6 carbon atoms,(ii) a polyol, (iii) DEGEE, benzyl alcohol, or both, and (iv) a fattyacid comprising between about 13-22 carbon atoms or a buffer. In thisembodiment of a quaternary solvent system, the monohydric alcohol,polyol and DEGEE or benzyl alcohol or both are as described above forthe ternary solvent system, with the additional feature that a fattyacid comprising between about 13-22 carbon atoms or a buffer is added tothe system. In embodiments where a fatty acid comprising between about13-22 carbon atoms is included in the solvent system, the fatty acid canbe, in one embodiment, a saturated fatty acid. Exemplary saturated fattyacids include myristic acid (C14), isopropylmyristic acid, palmitic acid(C16), stearic acid (C18) and arachidic acid (C22). In an exemplaryembodiment, the saturated fatty acid is isostearic acid. In oneembodiment, the exemplary quaternary solvent system additionallycomprises phenoxyethanol, rendering the system a quinary solvent system.The phenoxyethanol is present in the system in an amount between about0.01-3 wt % or between about 0.07-2 wt %.

The composition, in one embodiment, can comprise a substance to increaseviscosity, sometimes referred to as a thickening agent or gelling agent.Exemplary agents include gums (e.g., xanthan gum, guar gum), pectins,starches, and synthetic polymers, such as polyacrylic acid andhydroxyalkylcelluloses, such as hydroxyethylcellulose,hydropropylcellulose, and hydroxypropylmethylcellulose. The amount ofviscosity increasing agent in the composition can range from about0.5-10 wt %, preferably between about 0.5-5 wt % or about 0.5-3 wt %. Inone embodiment, the thickening agent is hydroxyethylcellulose, and inanother embodiment is hydroxyethylcellulose with a molecular weight ofbetween about 800,000-1,250,000 Daltons.

Using these guiding principles, the intracutaneous delivery of patidegibinto human skin from the five formulations set forth in Table 1 wastested in vitro using human skin in a Franz diffusion cell. As aninitial indicator of partitioning of patidegib from the testformulations into the stratum corneum, the concentration of patidegib inthe receiver fluid of each Franz cell was measured by taking aliquots ofreceiver fluid at various time points between 14-48 hours. After the 48hour topical application to the skin, the layers of the skin wereindividually analyzed for concentration of patidegib in the stratumcorneum, epidermis and dermis to assess intracutaneous delivery. Theresults are shown in FIGS. 1A-1B.

FIG. 1A shows the cumulative amount of patidegib permeated across humanskin in vitro, in ng/cm², as a function of time, in hours, for the fivecompositions of patidegib in the exemplary solvent systems set forth inTable 1. The formulations identified as SS5 (open squares), SS6 (closedtriangles), SS20 (x symbols) and SS14 (closed diamonds) each provided acumulative amount of patidegib of at least about 250 ng/cm² in 24 hours.Two of the formulations, SS20 (x symbols) and SS14 (closed diamonds),achieved a cumulative amount of patidegib of at least about 500 ng/cm²in 36 hours. The formulation identified as SS14 achieved a cumulativeamount of patidegib of at least about 1000 ng/cm² in 36 hours. Thenon-aqueous formulation, SS22 (open diamonds), had the lowest flux ofpatidegib of the formulations tested, yet provided a cumulative amountdelivered across the skin of about 250 ng/cm² in 40 hours.

The desired topical formulation is one that achieves partitioning of thehedgehog inhibitor compound from the topical formulation into thestratum corneum, diffusion across the stratum corneum, and retention inthe epidermis and/or dermis. Thus, to assess the ability of theformulations to achieve intracutaneous delivery rather than transdermaldelivery, the concentration of hedgehog inhibitor compound in thestratum corneum, epidermis and dermis was measured after 48 hourstopical exposure to the test formulations. Results of the analysis ofthe layers of the skin for concentration of patidegib are shown in FIG.1B. The amount of patidegib delivered to the dermis (bars with diagonalfill) was highest for the formulations identified as SS6 and SS14, whicheach provided greater than 5000 ng patidegib to the dermis after 48hours of topical application. The formulation identified as SS22delivered greater than 7000 ng of patidegib to the epidermis (bars withhorizontal fill) after 48 hours of contact with the skin.

Accordingly, in one embodiment, a topical formulation of patidegib isprovided that achieves after 24 hours or after 48 hours of topicalapplication in vitro an amount of patidegib in the epidermis, the dermisor the epidermis and dermis combined that exceeds the amount ofpatidegib in the stratum corneum. In another embodiment, a topicalformulation of patidegib is provided that achieves after 24 hours orafter 48 hours of topical application in vitro an amount of patidegib inthe epidermis, the dermis, or the epidermis and dermis combined thatexceeds by at least about 15%, 25% or 40% the amount of patidegib in thestratum corneum. In another embodiment, a topical formulation ofpatidegib is provided that achieves after 24 hours or after 48 hours oftopical application in vitro an amount of patidegib in the epidermis,the dermis, or the epidermis and dermis combined that exceeds by atleast about 150%, 200%, 300%, 350% or 400% the amount of patidegib inthe receiver fluid. In another embodiment, a topical formulation ofpatidegib is provided that achieves after 24 hours or after 48 hours oftopical application in vitro an amount of patidegib in the epidermis,the dermis, or the epidermis and dermis combined that is at least about1.5, 2, 3, 3.5, 4 or 5 fold greater than the amount of patidegib in thereceiver fluid.

The drug in each layer of the skin is tabulated in Table 2 inconcentration units of micromolar.

TABLE 2 Concentration of patidegib (μM) in each of the stratum corneum,epidermis and dermis 48 hours after topical application. Concentrationof Concentration of Concentration of patidegib (μM) in patidegib (μM) inpatidegib (μM) Formulation stratum corneum. epidermis in dermis SS517080 1233 445 SS6 12593 1039 629 SS14 13238 1851 823 SS20 6588 1057 521SS22 12880 2425 367

The half maximal effective concentration of patidegib for inhibition ofcellular hedgehog pathway is 0.007 μM (Tremblay et al., J. Med. Chem.,52(14):4400-44118 (2009)). The formulations identified herein as SS5,SS6, SS14, SS20 and SS22 each provided for delivery of patidegib to theepidermis or dermis in an amount sufficient for therapy; that is, in oneembodiment, an amount that provides a half-maximal effectiveconcentration in the dermis, epidermis or combined dermis and epidermiswithin about 24 hours after topical application of the composition.

As mentioned above, the compound is included in the composition in anamount between about 0.1-10 wt %, or between about 1-10 wt %,alternatively between about 2-8 wt % or about 3-7 wt %. It will beappreciated that adjustments to the amount of compound added may varyaccording to the potency of the compound, although the weight percent ofcompound in the final formulation will typically be within the statedranges.

In another study, detailed in Example 2, additional topical compositionswere prepared and the delivery of patidegib from each was studied invitro. The topical compositions of this study were variations of theformulations identified above as SS14 and SS22, which are included inTable 3 below for ease of reference.

TABLE 3 Exemplary Topical Compositions Non-aqueous Aqueous FormulationsFormulations SS14 SS14.10 SS14.19 SS22 SS22.7 SS22.9 wt % wt % wt % wt %wt % wt % ethanol 23.5 7.4 — 47.3 — — isopropyl alcohol — — — — 49.149.5 propylene glycol 18.8 4.9 — 30.3 31.4 — benzyl alcohol — — — 1.9 —— DEGEE* 18.8 9.8 — isostearic acid — — — 14.2 16.7 24.7 isopropylmyristate — — — — — 23.7 phenoxyethanol 0.9 1.0 1.0 buffer 31.0 — — — —— deionized water — 74.2 96.9 — — — hydroxypropyl 2.0 2.0 2.0 2.0 2.02.0 cellulose patidegib 5.0 0.75 0.1 4.4 0.75 0.1 Ratio monohydric 1.251.51 0 1.6 1.6 0 alcohol/diol *DEGEE = diethylene glycol monoethyl ether(Transcutol ® P)

The intracutaneous delivery of patidegib from the formulations set forthin Table 3 was tested in vitro using human skin. As an initial indicatorof partitioning of patidegib from the formulation into the stratumcorneum, the concentration of patidegib in the receiver fluid of theFranz cell was measured by taking aliquots of receiver fluid at varioustime points between 14-48 hours. After the 48 hour topical applicationto the skin, the layers of the skin were analyzed for drug concentrationto measure intracutaneous delivery. The results are shown in FIGS.2A-21B. FIG. 2A shows the cumulative amount of patidegib permeatedacross human skin in vitro, in ng/cm², as a function of time, in hours.The non-aqueous formulation SS22 (open diamonds) and the aqueousformulation SS14 (closed diamonds) achieved the highest permeation ofpatidegib with at least about 500 ng/cm² in 24 hours and at least about1000 ng/cm² in 36 hours. The study reveals that decreasing theconcentration of hedgehog inhibitor compound decreases the cumulativeamount delivered across the skin in both the aqueous and non-aqueousformulations (e.g., compare SS22.7 (non-aqueous, closed triangles) andSS14.10 (aqueous, open triangles)). Formulations with no diol, and thusa ratio of monohydric alcohol to diol of zero, and with 0.1 wt %patidegib had the lowest amount of patidegib delivered across the skin(e.g., SS22.9 (open circles) and SS14.19 (closed circles)).

At the end of the 48 hour in vitro permeation investigation, the skinwas removed from the Franz diffusion cells and analyzed for patidegibconcentration in the layers of the skin. The results are shown in FIG.2B, where the bars for each formulation correspond to stratum corneum(dashes), epidermis (horizontal fill), dermis (diagonal fill) andreceiver fluid (dots). The amount of patidegib delivered to the dermis(bars with diagonal fill) was highest for the formulations identified asSS14 and SS22, which each provided greater than 2900 ng of patidegib tothe dermis after 48 hours of topical application. The formulationidentified as SS22 delivered greater than 5000 ng of patidegib to theepidermis (bars with horizontal fill) after 48 hours of contact with theskin. The formulations with less than 1 wt % drug compound (SS14.10,SS14.19, SS22.7 and SS22.9) delivered less than about 1000 ng of drug tothe epidermis or dermis after 48 hour topical application.

The drug in each layer of the skin is tabulated in Table 4 inconcentration units of micromolar (μM).

TABLE 4 Concentration of patidegib (μM) in each of the stratum corneum,epidermis and dermis 48 hours after topical application. ConcentrationConcentration Concentration Concentration of patidegib of patidegib ofpatidegib Formu- of patidegib (μM) in Stratum (μM) in (μM) in lation (%w/w) corneum epidermis dermis SS14 4.97 37819 758 341 SS14.10 0.75 2687315 50 SS14.19 0.10 215 35 5 SS22 4.35 51911 2458 349 SS22.7 0.75 1538287 53 SS22.9 0.10 459 26 9

Accordingly, in one embodiment, the topical composition is one where thehedgehog inhibitor compound has a saturation solubility in the solventsystem of between about 0.1-10 wt %, alternatively between about 2.5-8wt %, and the solvent system comprises between about 15-60 wt % ethanoland between about 10-50 wt % propylene glycol. In another embodiment,the hedgehog inhibitor compound has a saturation solubility in thesolvent system of between about 0.1-10 wt % or between about 2.5-8 wt %and is present in the composition in an amount between about 0.1-10 wt %or between about 2-8 wt %, or between about 2.5-7 wt %, or between about2.8-7.5 or between about 3.0-7.0 wt %.

In another embodiment, the concentration of hedgehog inhibitor compoundis between about 0.1-10 wt % or between about 2-8 wt %, between about2.5-7 wt %, between about 2.8-7.5 or between about 3.0-7.0 wt %.

In another study, detailed in Example 3, the formulations identified asSS14 and SS22 were prepared with lower amount of patidegib and tested invitro using human skin in a Franz diffusion cell. The aqueousformulation SS14 comprises of about 5 wt % patidegib and two comparativeformulations were prepared that had 0.75 wt % (SS14D2) and 0.1 wt %(SS14D1) patidegib. The non-aqueous formulation SS22 comprises about 4.4wt % patidegib and two comparative formulations were prepared that had0.75 wt % (SS22D2) and 0.1 wt % (SS14D1) patidegib. The compositions areset forth in Example 3.

As an initial indicator of partitioning of patidegib from theformulation into the stratum corneum, the concentration of patidegib inthe receiver fluid of the Franz cell was measured by taking aliquots ofreceiver fluid at various time points between 14-48 hours. After the 48hour topical application to the skin, the layers of the skin wereanalyzed for drug concentration to measure intracutaneous delivery. Theresults are shown in FIGS. 3A-3B. FIG. 3A shows the cumulative amount ofpatidegib permeated across human skin in vitro, in ng/cm², as a functionof time, in hours. The non-aqueous formulation SS22 (open diamonds)achieved the highest cumulative amount of patidegib permeated across theskin, with at least about 750 ng/cm² in 24 hours and at least about 1000ng/cm² in 36 hours. The aqueous formulations SS14 (closed diamonds),SS14D1 (closed circles) and SS14D2 (closed squares) yielded a highercumulative amount of patidegib permeated across the skin relative to thenon-aqueous formulations with 0.75 wt % and 0.1 wt % patidegib(respectively, SS22D2, open squares and SS22D1, open circles). The studyconfirms the results observed in Examples 1 and 2 that the topicalcompositions with at least about 2 wt % drug compound, preferably atleast about 2.5 wt % drug compound in a solvent system with a monohydricalcohol and a diol in a ratio of between about 1.0-1.8 or 1.2-1.6provide a topical composition that when applied to the skin of a subjectin need delivers a therapeutically effective amount at times between10-60 hours after topical application, or at times of 10-50 hours, or12-48 hours.

At the end of the 48 hour in vitro permeation investigation, the skinwas removed from the Franz diffusion cells and analyzed for patidegibconcentration in the layers of the skin. The results are shown in FIG.3B, where the bars for each formulation correspond to stratum corneum(dashes), epidermis (horizontal fill), dermis (diagonal fill) andreceiver fluid (dots). The amount of patidegib delivered to the dermis(bars with diagonal fill) was highest for the formulations identified asSS14 and SS22, which each provided greater than 3000 ng patidegib to thedermis after 48 hours of topical application. The formulation identifiedas SS22 delivered more drug to the dermis (bars with diagonal fill) thanthe epidermis (bars with horizontal fill) after 48 hours of contact withthe skin. The formulations with less than 1 wt % drug compound (SS14D1,SS14D2, SS22D1 and SS22D2) delivered less than about 1000 ng of drug tothe dermis after 48 hours topical application.

Accordingly, in one embodiment, a topical formulation of patidegib isprovided that achieves after 24 hours or after 48 hours of topicalapplication in vitro an amount of patidegib in the epidermis, the dermisor the epidermis and dermis combined that exceeds the amount ofpatidegib in the stratum corneum. In another embodiment, a topicalformulation of patidegib is provided that achieves after 24 hours orafter 48 hours of topical application in vitro an amount of patidegib inthe epidermis, the dermis, or the epidermis and dermis combined thatexceeds by at least about 15%, 25% or 40% the amount of patidegib in thestratum corneum. In another embodiment, a topical formulation ofpatidegib is provided that achieves after 24 hours or after 48 hours oftopical application in vitro an amount of patidegib in the epidermis,the dermis, or the epidermis and dermis combined that exceeds by atleast about 150%, 200%, 300%, 350% or 400% the amount of patidegib inthe receiver fluid. In another embodiment, a topical formulation ofpatidegib is provided that achieves after 24 hours or after 48 hours oftopical application in vitro an amount of patidegib in the epidermis,the dermis, or the epidermis and dermis combined that is at least about1.5, 2, 3, 3.5, 4 or 5 fold greater than the amount of patidegib in thereceiver fluid.

The drug in each layer of the skin is tabulated in Table 5 inconcentration units of micromolar (μM).

TABLE 5 Concentration of patidegib (μM) in each of the stratum corneum,epidermis and dermis 48 hours after topical application. ConcentrationConcentration Concentration Concentration of patidegib of patidegib ofpatidegib Formu- of patidegib (μM) in Stratum (μM) (μM) lation (% w/w)corneum in epidermis in dermis SS14 4.97 16226 1470 401 SS14D1 0.10 553247 35 SS14D2 0.75 3245 534 81 SS22 4.35 7329 1093 415 SS22D1 0.10 28649 5 SS22D2 0.75 3118 597 107

The stability of several exemplary formulations was studied, as detailedin Example 4. The formulations detailed in Example 1 were stored forfour weeks storage at 25° C. and at 40° C. and stability was assessed byanalyzing the formulations for patidegib content. The results showedthat the formulations were stable at room temperature (20-25° C.) and upto 40° C. for at least about 4 weeks, as evidenced by no degradation ofpatidegib. Accordingly, in one embodiment, compositions are providedthat are stable, as evidenced by the patidegib content being between95-105% of the theoretical patidegib content and/or the patidegibcontent at time zero (t=0), at room temperature.

In one embodiment, the formulation is an alcoholic solution. In such aformulation, the carrier is typically an admixture of monohydroxyalcohols and polyols. The formulation may optionally contain at leastone penetration enhancer. Examples of suitable monohydroxy alcoholsinclude, for example, ethanol, propanol, butanol and benzyl alcohol.Reference herein to “ethanol” includes absolute alcohol, as well as“alcohol USP” and all denatured forms of 95% ethanol. As used herein,the term “propanol” refers to all isomeric forms, including n-propanoland isopropanol, and the term “butanol” refers to all isomeric forms,including, for example, n-butanol, iso-butanol and sec-butanol. In oneembodiment, the alcohol is selected from the group comprising ethanol,isopropyl alcohol, and benzyl alcohol, with ethanol being particularlyuseful.

Examples of suitable polyols include, for example, propylene glycol,dipropylene glycol, hexylene glycol, 1,3-butylene glycol, liquidpolyethylene glycols, such as polyethylene glycol200 (PEG-200) andpolyethylene glycol400 (PEG-400). A particularly useful polyol ispropylene glycol.

For those formulations that are alcoholic solutions or aqueous-alcoholicsolutions, the polyol will typically be present in the quantity of fromabout 0 to about 80% w/w, more typically about 10 to about 25% w/w. Themonohydroxy alcohol will be present in the quantity of about 10 to about99.9% w/w, more typically from about 40 to about 90% w/w. One example ofsuch an alcoholic solution is a formulation containing about 1% w/v ofCompound, about 10 to 30% w/w of a polyol, and about 40 to about 90% w/wof a monohydroxy alcohol.

Minor amounts of water can also be included in the formulation.Optionally a penetration enhancer may be incorporated into thesealcoholic solutions. In one embodiment, the formulation contains fromabout 10% to about 25% (w/w) of a polyol, from about 50% to about 70%(w/w) of a monohydroxy alcohol and from about 1% to about 30% (w/w) of apenetration enhancer. In a second embodiment, the formulation containsfrom about 10% to about 25% (w/w) of a polyol selected from the groupconsisting of propylene glycol, dipropylene glycol, hexylene glycol,1,3-butylene glycol, polyethylene glycol, and glycerol, from about 50%to about 70% (w/w) of a monohydroxy alcohol selected from the groupconsisting of ethanol, isopropyl alcohol and benzyl alcohol and fromabout 1% to about 30% (w/w) of a penetration enhancer selected from thegroup consisting of isopropyl myristate, cyclopentadecanolide andpropylene glycol dicaprylate/dicaprate. In a more specific embodiment,the formulation contains from about 10% to about 25% (w/w) of propyleneglycol, from about 50% to about 70% (w/w) of ethanol, and from about 1%to about 30% (w/w) of isopropyl myristate. More specifically, theformulation contains about 0.5 to about 3 w/v % of Compound, about 20%(w/w) of a propylene glycol, about 60% (w/w) of ethanol and about 20%(w/w) of isopropyl myristate.

Additional studies were conducted on exemplary topical formulationscomprising the hedgehog inhibitor, itraconazole. Since itraconazole is apoorly water soluble drug, solubility studies were initially conductedto assess compound solubility in a variety of solvents. For ease ofreference, the following formulation descriptions are described in thecontext of itraconazole as the hedgehog inhibitor compound, although anysuitable hedgehog inhibitor compound, in particular those havingstructural and physicochemical properties similar to itraconazole may beused. Following initial screening experiments, an initial set of 13preliminarily optimized formulations was prepared comprising variouscombinations of solvents and system components as described in Example6. The combination of solvents selected for the initially optimizedformulations were determined based upon solubility of the hedgehoginhibitor compound, e.g., itraconazole, stability of drug in theformulation upon storage, solvent compatibility. An additionalconsideration is skin permeability to achieve a localized skin effectwith minimal or no systemic absorption (to be described in greaterdetail below). The solvent systems explored in Example 6 demonstratedacceptable solvent compatibility and drug stability results, and werethen reformulated as non-aqueous gels for topical administration.Formulations for topical delivery may be in any form suitable forapplication to the skin, e.g., may be in the form of liquids, gels,ointments, creams, aerosols, and the like.

Based upon extensive screening studies, certain features of preferredtopical formulations were determined. Topical formulations foradministering a hedgehog inhibitor compound comprise a solvent system asfollows. In one or more embodiments, the solvent system comprises analiphatic monohydric alcohol having between 1-6 carbon atoms and a loweralkyl end-capped oligomeric alkylene glycol in a w/w ratio of betweenabout 0.8 and 2.6. Suitable monohydric alcohols are as described above.For example, in one or more embodiments, the monohydric alcohol is aprimary aliphatic alcohol selected from methanol, ethanol, 1-propanol,butanol, amyl alcohol (pentanol) and hexanol. Alternatively, themonohydric alcohol is a secondary alcohol such as isopropyl alcohol, orsec-butyl alcohol. In yet another embodiment, the monohydric alcohol isone having 2-4 or 2-3 carbon atoms. Exemplary solvent systems are atleast ternary solvent systems comprising three different solvents eachpresent in the solvent system in a w/w percentage greater than 10 weightpercent. Thus, in reference to formulations directed to the exemplaryhedgehog inhibitor, itraconazole, a binary solvent system, or a ternarysolvent system, or a quaternary solvent system is one in which only twosolvents, or only three solvents, or only four solvents, respectively,is present in an amount greater than 10 w/w percent. The w/w ratio ofmonohydric alcohol to lower alkyl end-capped oligomeric alkylene glycolis typically between 0.8 and 2.6, or is preferably between about 1.0 and2.4, or more preferably from 1.0 and 2.3. Exemplary w/w ratios include0.85, 0.90, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.1, 2.2, 2.3, 2.4, and 2.5, including any and all ranges in between anytwo of the foregoing values.

One illustrative lower alkyl end-capped oligomeric alkylene glycolsuitable for use in the instant compositions (with any of the hedgehoginhibitor compounds disclosed herein) is diethylene glycol monoethylether (DEGEE). In one or more embodiments, the lower alkyl end-cappedoligomeric alkylene glycol is end-capped with a lower alkyl group, i.e.,an aliphatic C1-C6 group, modifying the terminal hydroxyl group. In thisembodiment, the oligomeric alkylene glyol is end-capped with a methoxy,ethoxy, propyloxy, butoxy, pentoxy, or hexoxy group. The oligomericalkylene glycol comprises from 2 to 13 alkylene glycol repeat units.Illustrative alkylene glycol repeat units include, for example, ethyleneoxide (—CH₂CH₂O—)_(n) and propylene oxide (—CH₂CCHCH₃O—)_(n) repeatunits, where n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and13. A preferred oligomeric alkylene glycol contains ethylene oxiderepeats. In one or more embodiments, the lower alkyl end-cappedoligomeric alkylene glycol is diethylene glycol HO—(CH₂CH₂O)₂—R, where Ris a lower alkyl group. Preferred lower alkyl end-capping groups, R areethyl and methyl.

In some embodiments, a ternary solvent system comprises an aliphaticmonohydric alcohol having between 1-6 carbon atoms and a non-end-cappedoligomeric alkylene glycol (instead of a lower alkyl end-cappedoligomeric alkylene glycol) in a w/w ratio of between about 0.8 and 2.6.Representative non-end capped oligomeric alkyene glycols include diolssuch as oligomeric PEG, and oligomeric polypropylene glycol. See, forexample, formulation SS40-I or IG. As described above, an oligomericalkylene glycol comprises from 2 to 13 alkylene glycol repeat units.Illustrative alkylene glycol repeat units include ethylene oxide(—CH₂CH₂O—)_(n) and propylene oxide (—CH₂CH₂CH₂O—)_(n) repeat units,where n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13. Apreferred oligomeric alkylene glycol contains ethylene oxide repeats. Inone or more embodiments, the non-end capped oligomeric alkylene glycolis oligomeric PEG. The oligomeric PEG typically possesses a numberaverage molecular weight between about 300 and 600, or between about 300and 500. A preferred oligomeric PEG is PEG-400, having a number averagemolecular weight of 400 (M_(n) 380-420). While oligomeric PEGs having asmall number of monomer repeats may be provided as monodispersecompounds, typically, oligomeric PEGs having 5 to 13 repeat units areprovided as polydisperse compounds, where the molecular weight providedis a number average molecular weight unless otherwise indicated.Oligomeric PEGs, both end-capped and non-end capped are commerciallyavailable. Representative amounts of an end-capped oligomeric alkyleneglycol as described herein apply equally to formulations in which theend-capped oligomeric alkylene glycol (e.g., DEGMEE) is replaced by anon-end capped oligomeric alkyelene glycol such as PEG.

The ternary solvent systems described above further comprise a fusedbicyclic ether having from 8-14 carbon atoms, where the number of carbonatoms refers to the total number of carbon atoms including anysubstituents. Generally, the fused bicyclic ether contains from 1 to 3oxygen atoms (e.g., 1, 2 or 3) in the bicyclic ring system (i.e., fusedoxacycles). Illustrative fused bicyclic systems include bicyclo [3.3.0]and [4.3.0] systems. The fused bicyclic ether possesses no unsaturation(i.e., is saturated), and may comprise from 1 to 4 substituentscovalently attached to the bicyclic ring system, where the substituentsare moieties that only contain atoms selected from carbon, hydrogen andoxygen. Illustrative substituents include alkyl groups, lower alkoxygroups, and hydroxyl groups. Representative fused bicyclic ethersinclude dianhydro-D-glucucitol, isosorbide dimethyl ether (synonymsinclude dimethyl isosorbide and1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitol), which possesses twomethoxy groups substituted on the dianhydro-D-glucitol ring system, andisosorbide diethyl ether.

In one or more embodiments, the w/w ratio of the lower alkyl end-cappedoligomeric alkylene glycol to the fused bicyclic ether having from 8-14carbon atoms is in a range between about 1 and 2.4, or between about 1and 2, or preferably between about 1.2 and 1.8, or in some instances, isabout 1.7. Exemplary w/w ratios include 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, and 2.3, including any and all ranges inbetween any two of the foregoing values.

In one or more embodiments, the composition comprises from about 70 w/w% to about 16 w/w % of an aliphatic monohydric primary alcohol, or fromabout 65 w/w % to about 18 w/w %, or preferably from about 60 w/w % toabout 20 w/w % of an aliphatic monohydric primary alcohol. In the eventthat the composition additionally comprises a non-aliphatic monohydricprimary alcohol such as benzyl alcohol, the total w/w percent ofmonohydric primary alcohol in the composition will increase accordingly.When present in the formulations, benzyl alcohol is typically present ata w/w percent that is less than ten percent. Thus, the above w/wpercentages for total w/w percent monohydric primary alcohol willincrease accordingly: 80 w/w % to about 26 w/w % of monohydric primaryalcohol, or from about 75 w/w % to about 28 w/w %, or preferably fromabout 70 w/w % to about 30 w/w % monohydric primary alcohol. Theserepresentative w/w percentages are considered to be disclosed incombination with any of the other illustrative w/w percentages ofadditional composition components described herein and/or disclosed incombination with any one or more of the w/w percentages disclosedherein.

In one or more alternative embodiments, e.g., when the solvent systemdoes not contain an N-substituted lactam, the composition comprises fromabout 70 w/w % to about 30 w/w % of an aliphatic monohydric primaryalcohol, or from about 65 w/w % to about 35 w/w %, or preferably fromabout 60 w/w % to about 40 w/w % of an aliphatic monohydric primaryalcohol. In the event that the composition additionally comprises anon-aliphatic monohydric primary alcohol such as benzyl alcohol, thetotal w/w percent of monohydric primary alcohol in the composition willincrease accordingly. These representative w/w percentages areconsidered to be disclosed in combination with any of the otherillustrative w/w percentages of additional composition componentsdescribed herein and/or disclosed in combination with any one or more ofthe w/w percentages or ranges disclosed herein.

In one or more additional embodiments, the composition comprises fromabout 16 w/w % to about 35 w/w %, or from about 20 w/w % to about 30 w/w% of the lower alkyl end-capped oligomeric alkylene glycol. Arepresentative about of the lower alkyl end-capped oligomeric alkyleneglycol is about 25 w/w %. These representative w/w percentages areconsidered to be disclosed in combination with any of the otherillustrative w/w percentages of additional composition componentsdescribed herein and/or disclosed in combination with any one or more ofthe w/w percentages or ranges disclosed herein.

In one or more embodiments, the combined percent by weight of the loweralkyl end-capped oligomeric alkylene glycol and the fused bicyclic etherhaving from 8-14 carbon atoms is from 30-50 w/w %. In certainrepresentative formulations, the combined percent by weight of theoptionally lower alkyl end-capped oligomeric alkylene glycol and thefused bicyclic ether having from 8-14 carbon atoms is 40 w/w %.

In further exemplary embodiments, the topical formulation comprises fromabout 7 w/w % to about 25 w/w %, or from about 10 w/w % to about 20 w/w% of a fused bicyclic ether having from 8-14 carbon atoms. In one ormore preferred embodiments, the w/w percent of the fused bicyclic etherhaving from 8-14 carbon atoms, e.g., dimethyl isosorbide, is less thanthe w/w percent of both the monohydric primary alcohol and the loweralkyl end-capped oligomeric alkylene glycol (e.g., DEGMEE). In one ormore embodiments, the w/w percent of the fused bicyclic ether havingfrom 8-14 carbon atoms is about 15 percent by weight.

In certain representative formulations, the ternary solvent system(i.e., composed of three solvents each present in greater than 10percent by weight) as described above consists essentially of ethanol,diethylene glycol monoethyl ether, and dimethyl isosorbide. See, forexample, compositions SS-37I (or IG, where G refers to gel) and SS-38I(or IG).

In an alternative illustrative formulation, the ternary solvent system(i.e., composed of three solvents each present in greater than 10percent by weight) as described above consists essentially of ethanol,oligomeric polyethylene glycol, and dimethyl isosorbide. See, forexample, composition SS-40I (or IG, where G refers to gel).

Generally, preferred compositions comprising itraconazole possesses asaturated solubility of itraconazole from about 0.14-1.5 w/w percent, ormore preferably, from about 0.25-1.0 w/w percent.

One solvent suitable for enhancing the solubility of itraconazole intopical formulations is N-methyl-2-pyrrolidone (“N-methyl pyrrolidone orNMP”). As noted in Example 6, itraconazole possesses a saturatedsolubility in N-methyl pyrrolidone of 7.65% w/w. Thus, certain topicalformulations of itraconazole comprise an N-substituted lactam having5-ring atoms, 6-ring atoms or 7-ring atoms. In certain embodiments, thenitrogen atom of the lactam is substituted with a methyl or with anethyl group (i.e., is an N-methyl or is an N-ethyl lactam). A preferredlactam is N-methyl pyrrolidone. See, e.g., formulation SS43-I or IG.

In certain formulations, the solvent system is a quaternary solventsystem comprising four different solvents each present in the solventsystem in a w/w percentage greater than 10 weight percent.Representative quaternary solvent systems include as one of the solventsan N-substituted lactam. Generally, such quaternary solvent systemsinclude a monohydric primary alcohol, a lower alkyl end-cappedoligomeric alkylene glycol, a fused bicyclic ether having from 8-14carbon atoms, and an N-substituted lactam as previously described. Inone or more embodiments of a quaternary solvent system, the w/w ratio ofthe monohydric primary alcohol and the lower alkyl end-capped oligomericalkylene glycol is between about 0.6 and 1.5, or is between about 0.8and 1.4, or is between about 0.9 and 1.3, or is between about 1.0 and1.5. In yet one or more further embodiments, the percentage by weight ofeach of the monohydric primary alcohol, the lower alkyl end-cappedoligomeric alkylene glycol, and N-vinyl pyrrolidone is from about 20-30.An exemplary quaternary solvent system consists essentially of ethanol,diethylene glycol monoethyl ether, dimethyl isosorbide, and N-methylpyrrolidone. In one or more embodiments of a quaternary solvent system,the percent by weight of the fused bicyclic ether having from 8-14carbon atoms is less than that of the monohydric primary alcohol, thelower alkyl end-capped oligomeric alkylene glycol, and the N-substitutedlactam. Representative quaternary solvent systems comprise from about 11w/w % to about 50 w/w %, or from about 15 w/w % to about 45 w/w %, oreven from about 20 w/w % to about 35 w/w % of the N-substituted lactam.In a preferred formulation, the w/w percent of N-methyl pyrrolidone inthe composition is about 25. As in all instances herein, therepresentative w/w percentages are considered to be disclosed incombination with any of the other illustrative w/w percentages ofadditional composition components described herein and/or disclosed incombination with any one or more of the w/w percentages or rangesdisclosed herein. In one or more embodiments of a quaternary solventsystem comprising an N-substituted lactam, the solvent system containsfrom about 40 w/w % to about 16 w/w % of an aliphatic monohydric primaryalcohol, or from about 17 w/w % to about 35 w/w %, or preferably fromabout 18 w/w % to about 30 w/w % of an aliphatic monohydric primaryalcohol.

An additional exemplary solvent system for topically administering ahedgehog inhibitor compound such as itraconazole comprises (i) a ternarycombination of low molecular weight aliphatic polyols having molecularweights ranging from 50 to 550), where the polyols possess 2 or 3hydroxyl groups, and a lower alkyl end-capped oligomeric alkylene glycolas described above in a w/w ratio of between about 1.5 and 2.4 and (ii)a fused bicyclic ether having from 8-14 carbon atoms (as describedabove). In certain embodiments of the foregoing, the solvent system isabsent an aliphatic monohydric alcohol such as ethanol.

Suitable aliphatic diols and triols include, for example, propyleneglycol, dipropylene glycol, hexylene glycol, 1,3-butylene glycol, liquidpolyethylene glycols, such as polyethylene glycol200 (PEG-200) andpolyethylene glycol400 (PEG-400), glycerol, trimethylolpropane, sorbitoland pentaerythritol. In one or more embodiments, the ternary combinationcontains two low molecular weight aliphatic polyols each containing 2-4carbon atoms. In certain embodiments, the ternary combination containstwo low molecular weight aliphatic polyols each containing three carbonatoms. In a particular embodiment, the ternary combination comprisesHOCH₂C(OH)HR′ where R′ is —CH₃ or —CH₂OH. In certain embodiments, theternary combination comprises glyercol and propylene glycol. In otherembodiments, the ternary combination further comprises a polyethyleneglycol, e.g., having a number average molecular weight from 300-500. Insome embodiments, the w/w ratio of the ternary combination of aliphaticpolyols to the lower alkyl end-capped oligomeric alkylene glycol is in arange from 1.8 to 2.1. For example, the ternary combination of aliphaticpolyols is present in the composition at a combined w/w percent betweenabout 35 and 60, or between about 40 and 55. In one or more furtherrepresentative embodiments, w/w ratio of propylene glycol to glycerol isbetween 1.5 and 2.5, and the w/w ratio of polyethylene glycol toglycerol is between 1.5 and 2.5. A representative formulation is SS-50Ior IG.

The instant formulations, and in particular, those particularly suitedfor administration of itraconazole, may, as described previously,further comprise benzyl alcohol. Benzyl alcohol, while not an aliphaticprimary alcohol, is a primary alcohol. Thus, in one or more embodiments,the monohydric alcohol component comprises, in addition to an aliphaticmonohydric primary alcohol, the primary alcohol benzyl alcohol. Whenpresent in the formulations, benzyl alcohol is typically present at aw/w percent that is less than ten percent. Illustrative amounts ofbenzyl alcohol include 1 w/w %, 2 w/w %, 3 w/w %, 4 w/w %, 5 w/w %, 6w/w %, 7 w/w %, 8 w/w %, and 9 w/w %. An exemplary about of benzylalcohol is 5 w/w percent. The addition of up to ten w/w percent benzylalcohol can be effective in increasing the concentration of itraconazolein the formulations. In some embodiments, the formulation does notcontain benzyl alcohol but does contain phenoxyethanol. In otherembodiments, the formulation does contain benzyl alcohol but does notcontain phenoxyethanol, a preservative. When contained in the instantformulations, the amount of phenoxyethanol is generally from about 0.01w/w % to about 5 w/w %, or is from about 0.5 w/w % to about 3 w/w %, oris even present in an amount between about 0.07-2 wt %. Illustrativeamounts of phenoxyethanol include the following percentages by weight:0.1, 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0.

A hedgehog inhibitor formulation, e.g., comprising itraconazole orpatidegib, may additionally contain small amounts, e.g., less than about10 w/w percent, of one or more additional additives, excipients,stabilizers, solvents, buffers, anti-oxidants, gel forming agents,preservatives, or the like. For example, in one or more embodiments, thecomposition comprises a small amount (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9w/w %) of an organic carbonate ester, preferably, a dialkyl carbonateester. Preferred are cyclic carbonate esters having a ring size from 4to 7 atoms. One exemplary cyclic carbonate ester is propylene carbonate.See, e.g., formulations SS38-I, SS40-I, SS43-I and SS50-I (or IG).

The instant formulations may also contain small amounts, e.g., from 0.01to 5 w/w %, more typically from 0.01 to 0.5 w/w % of an anti-oxidant.Exemplary anti-oxidants include, for example, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), ascorbic acid, tert-butylhydroquinone, propyl gallate, and the like. In one or more particularembodiments, a topical composition as described herein containsbutylated hydroxytoluene.

The compositions described may be in the form of solutions, suspensions,emulsions, ointments, lotions, gels, and the like. Emulsions of the formoil-in-water or water-in-oil are contemplated, particular fornon-itraconazole containing formulations. The compositions are topicallyapplied directly to the skin, for example, with the fingertips of asubject in need or by a caregiver, or for example, by spraying thesolution or suspension onto the skin.

Gels are formed by the entrapment of large amounts of aqueous oraqueous-alcoholic liquids in a network of colloidal solid particles.These colloids are typically present at concentrations of less than 10%w/w and are also referred to as gelling agents or thickening agents,also mentioned herein above. Examples of suitable gelling agents includecarboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, methyl cellulose, sodium alginate, alginic acid, pectin,tragacanth, carrageen, agar, clays, aluminium silicate, carbomers, etc.

For formulations comprising itraconazole, the gelling agenthydroxypropyl cellulose (HPC) is preferred, in particular for use informulations in which a smooth, non-particulate containing formulationis desired. Illustrative amounts of a gelling agent, as mentioned above,are typically less than 10 w/w %, and are often less than 5 w/w %. Forinstance, a formulation as provided herein may comprise 1, 2, 3, 4, or 5w/w percent of a gel forming agent. In some embodiments, the formulationcomprises from 1-3 w/w % of a gel forming agent. In one or moreembodiments, the hedgehog inhibitor is itraconazole and the thickeningagent is hydroxypropyl cellulose; in another embodiment, the hedgehoginhibitor is itraconazole and the thickening/gelling agent ishydroxypropylcellulose having a weight average molecular weight betweenabout 50,000 to 150,000 Daltons, or from about 60,000 to about 125,000Daltons, or preferably from about 80,000 to about 100,000 Daltons.

Creams and ointments may also be utilized. They are emulsions ofoleaginous substances and water (i.e. the carrier). The cream may be awater-in-oil (w/o) in which an aqueous phase is dispersed in an oilphase, or an oil-in-water (o/w) which have an oil dispersed within anaqueous base. An ointment is also contemplated, and is typically moreviscous than an o/w cream. Traditional ointment bases (i.e. the carrier)include hydrocarbons (petrolatum, beeswax, etc.) vegetable oils, fattyalcohols (cholesterol, lanolin, wool alcohol, stearyl alcohol, etc.) orsilicones. Pastes are a type of ointment into which a high percentage ofinsoluble particulate solids have been added, up to 50% by weight.Insoluble solids such as starch, zinc oxide, calcium carbonate, or talcmay be used.

Aerosols may also be utilized. The compound may be dissolved in apropellant and a co-solvent such ethanol, acetone, hexadecyl alcohol,etc. Foaming agents may be incorporated to produce a mousse.

In some embodiments directed to topical formulations in which thehedgehog inhibitor compound is itraconazole, the composition does notcontain a surfactant. In some other embodiments directed to topicalformulations comprising the hedgehog inhibitor, itraconazole, thecomposition is absent a triglyceride. In yet some further embodimentsrelated to topical formulations in which the hedgehog inhibitor compoundis itraconazole, the composition is absent a complexing agent such as acyclodextrin. In yet one or more further embodiments of a topicalformulation comprising the hedgehog inhibitor, itraconazole, thecomposition is not an oil-in-water emulsion and does not contain ahydrophobic oil. In certain further embodiments, theitraconazole-containing composition does not contain a surfactant, or atriglyceride, or a complexing agent, or a hydrophobic oil.

Formulations having the characteristics described herein, e.g., theparticular composition components and relative amounts and ranges ofeach, were devised based at least in part upon hedgehog inhibitorsolubility, as well as system compatibility, and stability of thehedgehog inhibitor in the formulation over time. Following aninvestigation of short-term stability, as described in detail in Example8, itraconazole-containing formulations having particular advantageousfeatures were further examined for their in-vitro skin permeation. Theseexemplary topical formulations are described in tabular form below. The“IG-2” designation of the samples refers to an itraconazole-containinggel formulation containing 2 w/w % of a gel forming agent.

TABLE 5-1 Exemplary Topical Compositions SS-37- SS-38 SS-40 SS-43 SS-50IG2 IG2 IG2** IG2 IG2 wt % wt % wt % wt % wt % ethanol 56.80 47.65 47.6522.20 — DEGEE 25.00 25.00 — 25.00 25.00 PEG-400 — — 25.00 — — N-methylpyrrolidone — — — 25.00 — TERNARY — — — — 10.00/ COMBINATION 19.75/Glycerol/propylene glycol/ 17.90 PEG-400 dimethyl isosorbide 15.00 15.0015.00 15.00 15.00 benzyl alcohol —  5.00  5.00  5.00  5.00phenoxyethanol  1.00 — — — — propylene carbonate —  5.00  5.00  5.00 5.00 Butylated hydroxytoluene  0.10  0.10  0.10  0.10  0.10hydroxypropyl cellulose  2.0   2.0   2.0   2.0   2.0  itraconazole  0.10 0.25  0.25  0.70  0.25 Ratio* monohydric alcohol/  2.27  2.11 —  1.09 —lower alkyl end capped oligomeric alkylene glycol *Includes ethanol andbenzyl alcohol **Ratio of monohydric alcohol/non-end capped oligomericalkylene glycol = 2.11

FIG. 4 shows the cumulative amount of itraconazole permeated acrosshuman skin in vitro, in ng/cm², as a function of time, in hours, for thefive compositions of itraconazole in the exemplary solvent systems setforth in Table 5-1. The formulations identified as SS50-IG2 (* symbols)and SS43-IG2 (x symbols) each provided a cumulative amount ofitraconazole of at least about 40 ng/cm² in 48 hours. The formulation,SS50-G2, had the highest flux of the formulations tested and alsoachieved the highest cumulative amount of itraconazole delivered acrossthe skin in 48 hours. Formulation SS43-IG2 exhibited the next highestflux and a similarly achieved the second highest cumulative amount ofitraconazole delivered across the skin in 48 hours. Two of theformulations, SS37-IG2 (closed squares) and SS38-IG2 (closed triangles),achieved a cumulative amount of itraconazole of at least about 10 ng/cm²in 48 hours. The formulation identified as SS4-IG2 (closed diamonds)achieved a cumulative amount of itrazonazole of at least about 3 ng/cm²in 48 hours. Thus, the instant topical formulations are capable ofpermeating through human skin and also of achieving concentrations ofitraconazole in the skin effective to achieve a cellular response.

To further assess the ability of the formulations to achieveintracutaneous delivery, the concentration of hedgehog inhibitorcompound (itraconazole) in the stratum corneum, epidermis and dermis wasmeasured after 48 hours topical exposure to the test formulations eachcomprising itraconazole. Results of the analysis of the layers of theskin for concentration of itraconazole are shown in FIG. 5. The amountof itraconazole delivered to the stratum corneum was highest for theformulation identified as SS43-IG2, which provided nearly 2000 ng(actual value 1973.01 ng) to the stratum corneum after 48 hours oftopical application. The same formulation, SS43-IG2, also delivered thehighest amount of itraconazole to both the epidermis (about 500 ng;actual value 503.54 ng) and the dermis (greater than 400 ng; actualvalue 427.93 ng) after 48 hours of topical application. The formulationsidentified as SS50-IG2 and SS38-IG2 also delivered beneficial levels ofitraconazole to each of the stratum corneum, the epidermis and thedermis.

The formulation identified as SS50-IG2 delivered about 900 ng (actualvalue 898.47 ng) of itrazonazole to the stratum corneum, about 210 ng(actual value 209.29 ng) to the epidermis, and about 230 ng (actualvalue 228.81 ng) to the dermis after 48 hours of contact with the skin.

The formulation identified as SS38-IG2 delivered about 900 ng (actualvalue 883.33 ng) of itrazonazole to the stratum corneum, about 425 ng(actual value 426.71 ng) to the epidermis, and about 150 ng (146.91 ng)to the dermis after 48 hours of contact with the skin.

The topical formulations described herein are effective to provide anabsolute concentration of hedgehog inhibitor compound such as patidegibor itraconazole in the living skin (epidermis and dermis) that issufficient to have a molecular effect, i.e., suppress hedgehogsignaling.

Accordingly, in one embodiment, a topical formulation of itraconazole isprovided that achieves after 48 hours of topical application in vitro anamount of itraconazole in the epidermis, the dermis, or the epidermisand dermis combined that exceeds by at least about 150%, 200%, 300%,350% or 400% the amount of itraconazole in the receiver fluid. Inanother embodiment, a topical formulation of itraconazole is providedthat achieves after 48 hours of topical application in vitro an amountof itraconazole in the epidermis, the dermis, or the epidermis anddermis combined that is at least about 1.5, 2, 3, 3.5, 4 or 5 foldgreater than the amount of itraconazole in the receiver fluid. Assupported by the concentration values of itraconazole in each of theskin matrices for representative topical compositions of itraconazole inTable 9, the formulations described herein are effective to achievetherapeutically effective levels of itraconazole in the skin, since theconcentrations of itraconazole achieved in each of the skin layersnotably exceeds the IC50 value for itraconazole (0.8 μM, Kim and Beachy,Cancer Cell, 17, 388-399, 2010).

A wide variety of methods may be used for preparing the formulationsdescribed above. Broadly speaking, the formulations may be prepared bycombining together the components of the formulations, as describedherein, at a temperature and for a time sufficient to provide apharmaceutically effective and elegant composition. The term “combiningtogether”, as used herein, means that all of the components of thecompositions may be combined and mixed together at about the same time.The term “combining together” also means that the various components maybe combined in one or more sequences to provide the desired product. Theformulation can be prepared on a weight/weight (w/w) or a weight/volume(w/v) basis depending upon the form of the final dosage form.

The compositions may be packaged for use in a medical setting or forretail distribution directly to the consumer (i.e., an article ofmanufacture or kit). Such articles will be labeled and packaged in amanner advising the patient how to use the product for therapy. Suchinstructions will include the duration of treatment, dosing schedule,precautions, etc. These instructions may be in the form of pictures,written instructions, or a combination thereof. They may be printed onthe side of the packaging, be an insert, or any other form ofcommunication appropriate for the retail market.

It will be appreciated that, in other embodiments, the compositions canbe incorporated into a topical delivery system that is applied to theskin. Topical delivery systems are well described in the literature andcan take the form of a reservoir type system with a backing membersecured to a membrane to device a reservoir for the composition. Anadhesive is included about the periphery of the membrane to secure thesystem to the skin. Other examples of delivery systems that may be usedfor topical application of the formulations described herein aresummarized, for example, in R. W. Baker and J. Farrant “Patents intransdermal drug delivery”, Drug Delivery Systems 1987 ConferenceProceedings, and the patents noted therein describing delivery devicesare incorporated by reference herein.

C. Methods of Treating

The compositions described herein are, in one aspect, for treating ahedgehog-associated cancer or tumor. The tumor can be a solid tumor, asoft tissue tumor, or a metastatic lesion. In one embodiment, thecompositions are for the treatment of skin cancer or more specificallyof squamous cell carcinoma, keratoacanthoma, melanoma, or basal cellcarcinoma. In one embodiment, the skin cancer is basal cell carcinoma.In yet a further embodiment, a method of treating a subject with Gorlinsyndrome is provided, where the subject presents with or is at risk ofpresenting with basal cell carcinoma.

For treatment of a skin cancer, the composition is applied topically tothe subject. In one embodiment, the topical application is to the regionof the skin presenting with a cancerous lesion, and in otherembodiments, the topical application is to a region of the skin that isnot presenting with a cancerous lesion—e.g., the composition is appliedtopically to healthy skin for prevention. In one particular embodiment,the composition is applied directly to the cancerous lesion.

For illustrative itraconazole based formulations, e.g., containing fromabout 0.1 to about 2 w/w % itraconazole, a single dose full faceapplication will typically correspond to about 0.1 mg to about 2 mg ofitraconazole, assuming application of approximately 125 milligrams ofgel to the face.

The composition is applied to the skin, in various embodiments, once amonth, once every two weeks, once every 10 days, once a week, twice aweek, three times a week, every other day, once daily, twice daily,three times daily or four times daily, etc. The dosing schedule willdepend, as can be appreciated, by factors well known in medical arts,including the dose of drug compound in the composition, the particularhedgehog inhibitor compound, additional therapeutic agents, if present,the type of cancer or condition to be treated, and the health of thepatient.

The methods and compositions can optionally be used in combination withone or more other cancer therapies (e.g., one or more therapeuticagents, surgery and/or radiation). In one or more embodiments, themethods and compositions are used in combination with a surgicalprocedure and/or radiation therapy. Surgical procedures include, but arenot limited to, excision, curettage and electrosurgery, cryosurgery,Mohs micrographic surgery, and laser surgery. Excision is useful forboth primary and recurrent tumors and has the advantage of allowing forhistological assessment of surgical margins. Curettage andelectrosurgery involves alternately removing soft tumor tissue with acurette and then destroying an extra margin of tissue byelectrodesiccation, electrocautery, or electrocoagulation. Cryosurgeryinvolves freezing the tumor to a temperature that kills the cells of thetumor. The dead tumor cells can be removed by, for example, curettage.Mohs micrographic surgery (MMS) involves a surgeon using a microscope toidentify the margin of the tumor more accurately and more precisely thanis possible by unaided visual inspection. MMS can increase thelikelihood that the entire tumor is removed and minimize the amount ofnormal tissue that is removed. Laser surgery involves using a laser tovaporize tumor cells or use of a laser in lieu of a scalpel blade forexcisional surgery.

In other embodiments, the methods and compositions provided herein areused in combination with one or more therapeutic agents. Any combinationof the hedgehog inhibitor composition and other cancer therapies (e.g.,one or more additional therapeutic agents, surgery and/or radiation) canbe used. For example, a topical hedgehog inhibitor composition asdescribed herein may comprise one or more additional therapeutic agents,or may be administered in conjunction with another type of therapy ortreatment. Additionally, the hedgehog inhibitor composition and/or othercancer therapies can be administered or carried out during periods ofactive disorder, or during a period of remission or less active disease.The hedgehog inhibitor composition and other cancer therapies asapplicable can be administered before treatment, concurrently withtreatment, post-treatment, or during remission of the disorder orcondition being treated. In one embodiment, the method or compositioncomprises a combination of patidegib and itraconazole.

In a further aspect, topically formulated itraconazole may beadministered in conjunction with another topical drug such as but notlimited to patidegib, to thereby prevent or inhibit degradation of thetopical drug (e.g., patidegib), e.g., by cytochrome-based degradationmechanisms, in the skin. By reducing its metabolism in the living skin,one may be able to provide a lower dose of patidegib (or another topicalagent) than could otherwise be achieved (e.g., in the absence of acombination with itraconazole) to achieve a therapeutically effectiveconcentration of drug in the skin. In one or more further relatedembodiments, topical patidegib, e.g., comprised within a composition ordelivery system as provided herein, is administered in conjunction withanother topical azole drug such as fluconazole, or ketoconazole, tothereby prevent or lessen degradation of the patidegib, e.g., bycytochrome-based degradation mechanisms, in the skin. The topicaladministration of an azole drug such as itraconazole may therefore beeffective to improve the efficacy of a topical or even systemicallyadministered drug such as patidegib due to local inhibition ofdegradation mechanisms that function to metabolize the drug in the skin.

A study was conducted to evaluate the toxicokinetics of patidegib whenadministered twice daily via dermal application for 13 weeks. Asdescribed in Example 11, the formulation identified herein as SS14 wasprepared, with patidegib concentrations of 2% and 4%. The formulations,along with a placebo, were applied topically to Gottingen Minipigs®twice daily, and blood samples were collected on study days 1, 14 and 90for analysis of patidegib and its metabolite, IPI-230.

The mean concentration-time profiles of patidegib in plasma for the testgroups (male and female results combined) are presented graphically inFIG. 6A and the mean concentration-time profiles of IPI-230 in plasmafor the test groups (male and female results combined) are presentedgraphically in FIG. 6B. The dose normalized C_(max) and AUC₀₋₂₄relationships of patidegib in Gottingen Minipig® plasma are presentedgraphically in for the combined sexes in FIGS. 7A-7B. After dermaladministration, patidegib was absorbed. Individual T_(max) values wereobserved 2 to 8 hours post the first or second dose on Day 1, and 2 to 6hours post the first or second dose on Days 14 and 90. The meanconcentration-time profiles for the combined sexes (FIG. 6A) show thatexposure to patidegib generally increased with the increase in doselevel from 40 to 80 mg/kg/day on Day 90. The data also shows that afterdermal administration of patidegib, IPI-230 appeared in plasma (FIG.6B). Individual T_(max) were observed 2 to 8 hours post the first orsecond daily dose on Days 14 and 90. The exposure, as assessed bypatidegib mean C_(max) and AUC₀₋₂₄ values, increased with the increasein patidegib dose level from 40 to 80 mg/kg/day on Day 90. The increasesin patidegib mean C_(max) and AUC₀₋₂₄ values were generally doseproportional, as presented FIGS. 7A-7B.

Exposure to patidegib increased with the increase in dose level from 40to 80 mg/kg/day on Day 90. The increases in patidegib mean C_(max) andAUC₀₋₂₄ values on Day 90 were generally greater than dose proportional.Patidegib mean C_(max) and AUC₀₋₂₄ values were generally greater than4-fold higher in females, when compared to males, on Days 14 and 90.Patidegib Day 14 to Day 1 ratio values ranged from 45.8 to 139 and from70.7 to 218 for mean C_(max) and AUC₀₋₂₄, respectively. Patidegib Day 90to Day 1 ratio values ranged from 7.89 to 28.4 and from 9.18 to 39.9 formean C_(max) and AUC₀₋₂₄, respectively. Additionally, mean C_(max) andAUC₀₋₂₄ were generally lower on Day 90 when compared to Day 14.

Exposure to the patidegib metabolite IPI-230 was demonstrated followingtwice daily administration of patidegib at 80 mg/kg/day on Days 14 and90. IPI-230 mean C_(max) and AUC₀₋₂₄ values were greater than 2-fold infemales when compared to males. Mean C_(max) and AUC₀₋₂₄ values couldnot be compared to Day 1, as Day 1 values for IPI-230 were generallybelow the limit of quantification (BLQ). The mean metabolite to parentratios ranged from 0.00535 to 0.00738 and from 0.00524 to 0.00702, forC_(max) and AUC₀₋₂₄, respectively. In summary, the study in Example 11demonstrated that exposure to patidegib increased with the increase indose level from 40 to 80 mg/kg/day on Day 90. Exposure to IPI-230 wasdemonstrated following twice daily administration of Patidegib at 80mg/kg/day on Days 14 and 90. The study also demonstrated that theincreases in patidegib mean C_(max) and AUC₀₋₂₄ values on Day 90 weregenerally dose proportional. Patidegib and IPI-230 mean C_(max) andAUC₀₋₂₄ values were generally greater than 2-fold higher in females whencompared to males. Patidegib Day 14 to Day 1 ratio values ranged from45.8 to 139 and from 70.7 to 218 for mean C_(max) and AUC₀₋₂₄,respectively. Patidegib Day 90 to Day 1 ratio values ranged from 7.89 to28.4 and from 9.18 to 39.9 for mean C_(max) and AUC₀₋₂₄, respectively.IPI-230 Day 14 and Day 90 mean C_(max) and AUC₀₋₂₄ values could not becompared to Day 1, as Day 1 values for IPI-230 were generally BLQ. Themean metabolite to parent ratios ranged from 0.00535 to 0.00738 and from0.00524 to 0.00702, for C_(max) and AUC₀₋₂₄, respectively.

III. Examples

The following examples are illustrative in nature and are in no wayintended to be limiting.

Example 1 Topical Formulations

The hedgehog inhibitor compound patidegib and the following solventsystems were prepared as topical formulations.

TABLE 1-1 Topical Formulation SS5 Ratio EtOH + Ratio Component w/w %BnOH/PG Ethanol/PG ethanol 18.73 1.1 1.0 propylene glycol 18.73 benzylalcohol 1.87 diethylene glycol monoethyl 18.73 ether* buffer, pH 7.535.59 hydroxypropyl cellulose 2.00 (HPC; Klucel HF grade) patidegib 4.35*abbreviated herein as “DEGEE” and also known as 2-(2-ethoxyethoxy)ethanol and sold under the tradename Transcutol ® P

TABLE 1-2 Topical Formulation SS6 Ratio EtOH + Ratio Component w/w %BnOH/PG Ethanol/PG ethanol 27.54 1.60 1.5 propylene glycol 18.36 benzylalcohol 1.84 diethylene glycol monoethyl ether 18.36 buffer, pH 7.525.70 hydroxypropyl cellulose 2.00 patidegib 6.21

TABLE 1-3 Topical Formulation SS14 Ratio Component w/w % Ethanol/PGethanol 23.49 1.25 propylene glycol 18.79 diethylene glycol monoethylether 18.79 buffer, pH 7.5 31.01 phenoxyethanol 0.94 hydroxypropylcellulose 2.00 patidegib 4.97

TABLE 1-4 Topical Formulation SS20 Ratio EtOH + Ratio Component w/w %BnOH/PG Ethanol/PG ethanol 23.81 1.35 1.25 propylene glycol 19.05 benzylalcohol 1.90 buffer, pH 7.5 49.52 hydroxypropyl cellulose 2.00 patidegib3.73

TABLE 1-5 Topical Formulation SS22 Ratio EtOH+ Ratio Component w/w %BnOH/PG Ethanol/PG ethanol 47.30 1.62 1.56 propylene glycol 30.27 benzylalcohol 1.89 isostearic acid 14.19 hydroxypropyl cellulose 2.00patidegib 4.35

The permeation of patidegib into human skin from the five formulationswas tested in vitro using Franz diffusion cells. Franz diffusion cellswith a surface area of about 0.6 cm² and a volume of 2.0 mL were used.Skin from an abdominoplasty was dermatomed to approximately 400micrometers (μm). The receiver side of the cell was filled withethanol/water 20/80 and the cells were maintained at 37±0.5° C. Eachtest formulation was dosed into the sample side of the cells using a 1mL plunger and positive displacement pipette. The weight of the plungerwas determined before and after dispensing formulation into each cell todispense a 6-7 mg dose of formulation (approximately 10 mg/cm²). Eachformulation was tested in six diffusion cells (n=6). A 200 μL aliquot ofreceiver fluid was removed from each cell at 0 hours, 14 hours, 18hours, 24 hours, 36 hours, 40 hours, 44 hours and 48 hours. Followingthe 48 hour time point, the Franz cells were dismantled to recover theskin for analysis. The concentration of patidegib in the stratumcorneum, epidermis and dermis was determined using tissue homogenizationand solvent extraction (80/20 v/v ethanol/water) and analysis via LCMS/MS. Results are shown in FIGS. 1A-1B.

Example 2 Topical Formulations

The hedgehog inhibitor compound patidegib and the following solventsystems were prepared as topical formulations.

TABLE 2-1 Topical Formulation SS14.10 Ratio Component w/w % Ethanol/PGethanol 7.37 1.50 propylene glycol 4.91 diethylene glycol monoethylether 9.83 (DEGEE) phenoxyethanol 0.98 deionized water 74.16hydroxypropyl cellulose 2.00 patidegib 0.75

TABLE 2-2 Topical Formulation SS14.19 Component w/w % phenoxyethanol0.99 deionized water 96.91 hydroxypropyl cellulose 2.00 patidegib 0.10

TABLE 2-3 Topical Formulation SS22.7 Ratio Component w/w % Ethanol/PGisopropyl alcohol 49.13 1.56 propylene glycol 31.44 isostearic acid16.68 hydroxypropyl cellulose 2.00 patidegib 0.75

TABLE 2-4 Topical Formulation SS22.9 Ratio Component w/w % Ethanol/PGisopropyl alcohol 49.45 0 propylene glycol — isostearic acid 24.72isopropyl myristate 23.74 hydroxypropyl cellulose 2.00 patidegib 0.10

The permeation of patidegib into human skin from the formulationsidentified in Example 1 as SS14 and SS22 and the formulations identifiedabove as SS14.10, SS 14.19, SS22.7 and SS22.9 were tested in vitro usingFranz diffusion cells. Franz diffusion cells with a surface area ofabout 0.6 cm² and a volume of 2.0 mL were used. Skin from anabdominoplasty was dermatomed to approximately 400 micrometers (m). Thereceiver side of the cell was filled with ethanol/water 20/80 and thecells were maintained at 37±0.5° C. Each test formulation was dosed intothe sample side of the cells using a 1 mL plunger and positivedisplacement pipette. The weight of the plunger was determined beforeand after dispensing formulation into each cell to dispense a 6-7 mgdose of formulation (approximately 10 mg/cm²). Each formulation wastested in six diffusion cells (n=6). A 200 μL aliquot of receiver fluidwas removed from each cell at 0 hours, 14 hours, 18 hours, 24 hours, 36hours, 40 hours, 44 hours and 48 hours. Following the 48 hour timepoint, the Franz cells were dismantled to recover the skin for analysis.The concentration of patidegib in the stratum corneum, epidermis anddermis was determined using tissue homogenization and solvent extraction(80/20 v/v ethanol/water). Results are shown in FIGS. 2A-2B.

Example 3 Topical Formulations with Patidegib

The hedgehog inhibitor compound patidegib and the following solventsystems were prepared as topical formulations.

TABLE 3-1 Topical Compositions Non-aqueous Aqueous FormulationsFormulations SS14 SS14D1 SS14D2 SS22 SS22D1 SS22D2 wt % wt % wt % wt %wt % wt % ethanol 23.5 23.5 23.5 47.3 47.3 47.3 propylene glycol 18.818.8 18.8 30.3 30.3 30.3 benzyl alcohol — — — 1.9 1.9 1.9 DEGEE* 18.818.8 18.8 isostearic acid — — — 14.2 18.4 17.8 phenoxyethanol 0.9 0.90.9 — — — buffer 31.0 35.9 35.2 — — — hydroxypropyl 2.0 2.0 2.0 2.0 2.02.0 cellulose patidegib 5.0 0.1 0.75 4.4 0.1 0.75 Ratio monohydric 1.251.25 1.25 1.62 1.62 1.62 alcohol/diol *DEGEE = diethylene glycolmonoethyl ether (Transcutol ® P)

The permeation of patidegib into human skin from the formulations wastested in vitro using Franz diffusion cells. Franz diffusion cells witha surface area of about 0.6 cm² and a volume of 2.0 mL were used. Skinfrom an abdominoplasty was dermatomed to approximately 400 micrometers(μm). The receiver side of the cell was filled with ethanol/water 20/80and the cells were maintained at 37±0.5° C. Each test formulation wasdosed into the sample side of the cells using a 1 mL plunger andpositive displacement pipette. The weight of the plunger was determinedbefore and after dispensing formulation into each cell to dispense a 6-7mg dose of formulation (approximately 10 mg/cm²). Each formulation wastested in six diffusion cells (n=6). A 200 μL aliquot of receiver fluidwas removed from each cell at 0 hours, 14 hours, 18 hours, 24 hours, 36hours, 40 hours, 44 hours and 48 hours. Following the 48 hour timepoint, the Franz cells were dismantled to recover the skin for analysis.The concentration of patidegib in the stratum corneum, epidermis anddermis was determined using tissue homogenization and solvent extraction(80/20 v/v ethanol/water). Results are shown in FIGS. 3A-3B.

Example 4 Stability of Exemplary Patidegib Topical Formulations

Stability of the exemplary formulations (SS5, SS6, SS14, SS20 and SS22)was assessed by analyzing the formulations for patidegib content afterfour weeks storage at 25° C. and at 40° C. Results are shown in thetables below.

TABLE 4-1 Stability of Exemplary Formulations—Mean Percentage Recoveryof Patidegib Mean percentage recovery of patidegib from theoretical (n =3, lowest-highest value) patidegib t = 22 weeks t = 4 weeks Formulation(% w/w) t = 0 25° C. 40° C. 25° C. 40° C. SS5 (Aq.) 4.35 97.88 109.82106.51 97.61 96.24 (95.44- (105.24- (106.25- (97.40- (95.59- 100.31)113.56) 106.64) 97.88) 97.06) SS6 (Aq.) 6.21 98.75 110.90 111.99 100.6097.75 (97.24- (109.77- (109.75- (99.11- (97.28- 100.28) 111.51) 114.30)102.79) 98.30) SS14 (Aq.) 4.97 102.44 131.46 105.62 99.07 96.63 (101.61-(127.08- (105.19- (98.39- (95.93- 103.61) 134.03) 106.25) 99.51) 97.85)SS20 (Aq.) 3.73 107.89 65.38 104.49 102.05 97.71 (107.11- (63.42-(103.57- (100.38- (97.10- 108.30) 67.35) 105.46) 103.72) 98.24) SS224.35 114.96 100.24 93.98 100.25 99.57 (Non-Aq.) (114.48- (99.66- (88.29-(100.18- (98.89- 115.40) 101.34) 103.31) 100.29) 99.93)

TABLE 4-2 Stability of Exemplary Formulations—Peak Purity of PatidegibMean percentage area/area of patidegib (n = 3, lowest-highest value)patidegib t = 2 weeks t = 4 weeks Formulation (% w/w) t = 0 25° C. 40°C. 25° C. 40° C. SS5 (Aq.) 4.35 99.49 99.63 99.52 99.28 99.30 (98.78-(99.60- (99.47- (99.26- (99.23- 99.87) 99.66) 99.60) 99.30) 99.38) SS6(Aq.) 6.21 100.00 99.71 99.41 99.08 99.25 (100.00- (99.68- (99.31-(99.00- (99.20- 100.00) 99.77) 99.48) 99.15) 99.28) SS14 (Aq.) 4.97100.00 99.67 99.49 99.33 99.28 (100.00- (99.65- (99.35- (99.32- (99.26-100.00) 99.69) 99.67) 99.33) 99.31) SS20 (Aq.) 3.73 99.89 99.67 99.4699.31 99.27 (99.88- (99.67- (99.33- (99.28- (99.23- 99.90) 99.67) 99.61)99.34) 99.31) SS22 4.35 100.00 99.94 99.95 99.92 99.84 (Non-Aq.)(100.00- (99.92 - (99.92- (99.91- (99.83- 100.00) 99.95) 99.98) 99.93)99.87)

TABLE 4-3 Stability of Exemplary Formulations SS14 and SS22—Peak Purityof Patidegib Storage Percentage patidegib peak purity (%) Formulationcondition (° C.) T = 0 T = 4 week T = 8 week SS14 25 99.72 99.82 99.8940 99.88 99.87 SS22 25 99.65 99.88 99.10 40 99.82 99.54

TABLE 4-4 Stability of Exemplary Formulations SS14 and SS22—MeanPercentage Recovery of Patidegib Storage condition Formulation (° C.) T= 0* T = 2 week T = 4 week T = 8 week SS14 25 100.61 109.04 103.44102.45 (99.81-101.30) (106.62-111.51) (102.99-103.85) (102.38-102.56) 40103.42 103.10 103.17 (102.23-104.59) (102.91-103.20) (102.13-104.40)SS22 25 95.78 98.51 99.90 97.74 (94.02-99.09) (98.13-99.19)(99.48-100.19) (97.46-98.03) 104.24 98.64 98.92 40 (102.30-106.85)(98.17-98.89) (98.51-99.28)

The patidegib content for all formulations at t=0 was between 97-117% ofthe theoretical concentration. The peak purity of the patidegibformulation at t=0 was greater than 99%. After 2 weeks of storage at 25°C. and at 40° C., the peak purity of all formulations were comparable tothe starting peak purity at t=0 and observed to be greater than 99%. Thepatidegib content for the formulations 2 weeks of storage at 25° C. andat 40° C. was between 65-131% of the theoretical concentration. After 4weeks of storage at 25° C. and at 40° C. the patidegib content of allformulations was between 95-105% of the theoretical concentration. Thepeak purity of all formulations was greater than 99% and comparable tothe peak purity at t=0, with the exception of SS5 at 40° C. which was98.58% and slightly lower than the t=0 value of 99.85%. Thus, theformulations are stable at room temperature (20-25° C.) and up to 40° C.for at least about 4 weeks.

Example 5 Skin Irritation of Exemplary Patidegib Topical Formulations

Skin irritation of three exemplary formulations prepared as described inExample 1 was assessed in Gottingen minipigs. The test formulationswere:

1. “SS22, 3.5 wt % patidegib”, and comprising ethanol, benzyl alcohol,isostearic acid and propylene glycol, and HPC as a gelling agent;

2. “SS14, low PG, 4.0 wt % patidegib”, and comprising Transcutol P,ethanol, propylene glycol, buffer (pH 7.5; boric acid and sodiumhydroxide) and phenoxyethanol and HPC as a gelling agent;

3. “SS14, 4.0 wt % patidegib”, and comprising Transcutol P, ethanol,propylene glycol, buffer (pH 7.5; boric acid and sodium hydroxide) andphenoxyethanol and HPC as a gelling agent;

4. SS22 placebo—same as formulation 1. above with no patidegib;

5. SS14, low PG placebo—same as formulation 2. above with no patidegib;

6. SS14 placebo—same as formulation 3. above with no patidegib;

In three minipigs, six application sites were identified; 3 sites oneach side of the midline of the dorsal region of each animal. Eachapplication measured 2×2 inches and the sites were marked at the cornerswith an indelible marker. Prior to administration, the hair was clippedfrom the back of each animal. Each test article and placebo (1 mL/site)was distributed over the prescribed area by gentle in junction with astainless steel spatula for 14 consecutive days. The test article wasapplied evenly with a thin, uniform film and the area was not occluded.For the initial dose, the material was applied in 0.25-0.5 mL/kgincrements until the maximum feasible volume was identified to be 1mL/kg application. Beginning on Day 2, the dosing sites were gentlywiped with a wiping cloth (WYPALL®) wet with tap water to remove anyresidual material.

Daily observations of the test sites on each pig were made. For the SS22formulation, very slight erythema was noted in 2/3 pigs beginning on Day2. This progressed to well-defined to moderate-to-server incidences ofthe course of the 14 days. By Day 14, very slight to moderate-to-severeerythema was present in all animals. Because the same observations weremade for the test and placebo SS22 test articles (numbers 1 and 4above), the erythema may be vehicle related rather than drug related.For the SS14 formulations (numbers 2, 3, 5 and 6 above), no erythema oredema was noted at any time point on either the active or placebo testsites.

Example 6 Combination Solvent Systems for Topical Administration of aHedgehog Inhibitor

The hedgehog inhibitor compound itraconazole and the following solventsystems were prepared as topical formulations. The solvent systems weredevised following solubility experiments in which the saturatedsolubility of itraconazole in various solvents after a minimum of 24hours stirring at 25° C. was investigated. Itraconazole is highlyinsoluble in water. However, following initial solubility experiments,itraconazole was found to exhibit a solubility between 0.01-0.05% w/w indimethicone 350 CST, diisopropyl adipate, ethanol and castor oil; indimethyl isosorbide, itraconazole exhibits a solubility of 2.32% w/w. Ahigher solubility was observed in benzyl alcohol and phenoxyethanol, of14.97% and 7.87% w/w, respectively. Itraconazole demonstrated asaturated solubility in N-methyl pyrrolidone of 7.65% w/w. For theremaining solvents in which itraconazole solubility was investigated(not shown), the drug possessed a solubility between 0.01-0.20% w/w.Following several screening studies in which various mixed solventsystems were explored to assess solubility, system compatibility, andstorage stability of itraconazole, the following optimized non-aqueousformulations were prepared.

TABLE 5-A Theoretical composition (%, w/w) Excipient SS36-I SS37-ISS38-I SS40-I SS42-I SS43-I Phenoxy- — 1 — — — — ethanol Benzyl 5 — 5 55 5 alcohol diethylene 25 25 25 — 25 25 glycol monoethyl ether Ethanol53.9 57.9 48.9 48.9 28.9 23.9 PEG 400 — — — 25 — — N-methyl — — — — 2525 pyrrolidone* dimethyliso- 15 15 15 15 15 15 sorbide Propylene — — 5 5— 5 Carbonate Butylated 0.1 0.1 0.1 0.1 0.1 0.1 hydroxy- toluene (BHT)Mean 0.34 0.16 0.34 0.33 0.76 0.86 itraconazole (0.23- (0.12- (0.30-(0.30- (0.72- (0.85- saturated 0.42) 0.19) 0.39) 0.37) 0.78) 0.88)solubility (%, w/w, lowest- highest value of n = 3) Mean 100.00 100.00100.00 100.00 100.00 100.00 itraconazole (100.00- (100.00- (100.00-(100.00- (100.00- (100.00- % area/area 100.00) 100.00) 100.00) 100.00)100.00) 100.00) (lowest- highest value of n = 3) Apparent 7.14 7.03 6.798.24 7.44 7.61 pH of solvent system with itraconazole*N-methy1-2-pyrrolidone, also known as N-methyl pyrrolidone, is soldunder the trade name Pharmasolve ™.

TABLE 5-B Theoretical composition (%, w/w) Excipient SS44-I SS45-ISS46-I SS47-I SS48-I SS49-I SS50-I Phenoxyethanol — — 1 — — — — Benzylalcohol 5 5 — 5 5 5 5 diethylene glycol 25 25 25 25 25 25 25 monoethylether Ethanol 53.9 53.9 32.9 23.9 23.9 — — Glycerol — — — — 10 10 10Propylene glycol — — — — 20 20 20 PEG 400 — 15 — 15 — 23.9 18.9N-methyl-2- — — 25 25 — — — pyrrolidone Dimethyl isosorbide 15 — 15 — 1515 15 Propylene Carbonate — — — 5 — — 5 Butylated — 0.1 0.1 0.1 0.1 0.10.1 hydroxytoluene Butylated 0.1 — — — — — — hydroxyanisol (BHA) Meanitraconazole 0.25 0.14 0.67 0.59 0.23 0.27 0.32 saturated solubility(0.22- (0.13- (0.64- (0.58- (0.22- (0.26- (0.31- (%, w/w, lowest- 0.27)0.15) 0.69) 0.59) 0.24) 0.29) 0.33) highest value of n = 3) Meanitraconazole 100.00 100.00 100.00 100.00 100.00 100.00 100.00 %area/area (lowest- (100.00- (100.00- (100.00- (100.00- (100.00- (100.00-(100.00- highest value of 100.00) 100.00) 100.00) 100.00) 100.00)100.00) 100.00) n = 3) Apparent pH of 7.04 8.88 7.33 9.26 6.8 7.7 7.61solvent system with itraconazole

The solubility of itraconazole in all of the additional solvent systemsgenerated (SS36-J to SS50-) was between about 0.24-0.86% w/w ofitraconazole, with the exception of SS37 and SS45 where the solubilitywas approximately 0.15% w/w of itraconazole. Topical formulations ofitraconazole will generally contain from about 0.10 w/w % itraconazoleto about 10 w/w % itraconazole, or more typically will contain fromabout 0.10 w/w % itraconazole to about 5 w/w % itraconacole, or moretypically from about 0.1-2 weight percent itraconazole.

Example 7 Non-Aqueous Gels for Topical Administration of a HedgehogInhibitor

Following the exploration and identification of the mixed solventsystems identified in Tables 5A and 5B, and following acceptable fourweek compatibility results, non-aqueous gels based on the formulationsdescribed in Example 6 were prepared. The gel formulations were slightlyviscous to highly viscous gels, with viscosity increasing with theamount of HPC in the solvent system (e.g., from 1% to 2% w/w). Basedupon initial formulation experiments, the gelling agents Carbopol 980and hydroxypropyl methylcellulose appeared to be incompatible withitraconazole and the solvent systems employed, with a white precipitateforming during formulation.

TABLE 6-A Representative Non-aqueous gels for Topical AdministrationTheoretical composition (%, w/w) SS36-IG SS37-IG SS38-IG SS40 SS42-IGSS43-IG Excipient 1% HPC P 1% HPC P 1% HPC P 1% HPC P 1% HPC P 1% HPC PPhenoxyethanol — 1 — — — — Benzyl alcohol 5 — 5 5 5 5 diethylene glycol25 25 25 — 25 25 monoethyl ether Ethanol 53.9 57.9 48.9 48.9 28.9 23.9PEG 400 — — — 25 — — N-methyl-2-pyrrolidone — — — — 25 25 Dimethylisosorbide 15 15 15 15 15 15 Propylene Carbonate — — 5 5 — 5 Butylated0.1 0.1 0.1 0.1 0.1 0.1 hydroxytoluene (BHT) Hydroxypropylcellulose 1 11 1 1 1 Apparent pH 7.03 7.06 7.24 8.31 7.74 7.84

TABLE 6-B Representative Non-Aqueous Gels for Topical AdministrationTheoretical composition (%, w/w) SS44-IG SS45-IG SS46-IG SS47-IG SS48-IGSS49-IG SS50-IG Excipient 1% HPC P 1% HPC P 1% HPC P 1% HPC P 1% HPC P1% HPC P 1% HPC P Phenoxyethanol — — 1 — — — — Benzyl alcohol 5 5 — 5 55 5 diethylene glycol 25 25 25 25 25 25 25 monoethyl ether Ethanol 53.953.9 32.9 23.9 23.9 — — Glycerol — — — — 10 10 10 Propylene glycol — — —— 20 20 20 PEG 400 — 15 — 15 — 23.9 18.9 N-methyl-2- — — 25 25 — — —pyrrolidone Dimethyl 15 — 15 — 15 15 15 isosorbide Propylene — — — 5 — —5 Carbonate Butylated — 0.1 0.1 0.1 0.1 0.1 0.1 hydroxytoluene Butylated0.1 — — — — — — hydroxyanisole Hydroxypropyl- 1 1 1 1 1 1 1 celluloseApparent pH 7.07 8.93 7.89 9.28 6.68 7.70 7.61

A representative active gel comprising itraconazole with 1.5% HPC and0.15% itraconazole was successfully formulated, forming a mediumviscosity gel with no appearance of itraconazole crystals when observedunder a microscope. Placebo gels were prepared for solvent systemsSS36-IG to SS50-IG and containing HPC at 1% w/w. In all cases, the gelsprepared were slightly hazy with a low to medium viscosity which flowedwhen tilted, with the exception of SS49 and SS50 which possessed amedium viscosity.

Example 8 Short-Term Stability of Non-Aqueous Gels for TopicalAdministration of a Hedgehog Inhibitor

A total of 16 formulations (including the corresponding placebos) wereprepared for short-term stability testing. The representativeformulations contain 2% w/w HPC (in contrast to the formulations abovewhich contain 1% w/w HPC), and comprise from 0.1% w/w to about 1.0% w/witraconazole. Only 14 of the 16 formulations prepared were placed onstability at 25 and 40° C. (and an additional temperature of 2-8° C.) inborosilicate glass vials, with the compositions of active formulationsoutlined in the tables below. The following tests were performed at eachtime point: 0, 2 and 4 weeks, for the assessment of the formulationsplaced on stability: visual appearance (macroscopic and microscopicappearance), apparent pH, and itraconazole content and peak purity.

Macroscopic Appearance

The formulations were visually assessed. At t=0, all active and placeboitraconazole gels were observed to be uniform, colourless with a highviscosity. Following 2 and 4 weeks storage at 25 and 40° C. allformulations were observed to be unchanged from t=0.

Microscopic Appearance

All formulations were assessed under the light microscope at 200 and400× magnification and compared to their respective placeboformulations. Crystallisation was not observed in any of the activeformulations at t=0 or following 2 and 4 weeks storage at 25 and 40° C.

Apparent pH

At t=0 the apparent pH of the itraconazole formulations was measured.The active itraconazole formulations possessed apparent pH valuesbetween 7.49 and 9.59 at t=0. Since all of the formulations placed onstability were non-aqueous based, the pH values are only “apparent pH”values, where the pH meter was standardized by use of an aqueous buffersolution. For the pH of the non-aqueous solutions, the ionizationconstant of the acid or base, the dielectric constant of the medium, theliquid junction potential (which may give rise to errors of 1 pH unit)and the hydrogen ion response of the glass electrode are all charged,giving rise to the “apparent pH”, which for the current purpose is tomonitor any pH changes during the stability program. After 2 weeksstored at 25 and 40° C., the apparent pH values of active and placeboformulations were relatively comparable to t=0 where the apparent pHvalues showed a small decrease in pH (up to 0.5 pH units). After 4 weeksstorage at 25 and 40° C. the apparent pH remained relatively comparableto t=2 weeks and t=0, with the final pH reading of each formulationfalling within 0.5 pH units of t=0, with the exception of SS43-IG whichwas within 0.7 pH units of the initial pH reading.

Itraconazole Content and Peak Purity

The formulations were analysed for itraconazole content. Itraconazolecontent for all of the active formulations prepared for short termstability was 95-102% of the theoretical concentration. Peak purity ofthe itraconazole formulations at t=0 were all >99.39%. After 2 weeksstorage at 25 and 40° C., the recovery and peak purity of allformulations were comparable to t=0, with the exception of SS33 at bothtemperatures and SS46-SS50 at 40° C. where a slight decrease initraconazole recovery (approx. 92-96%) was observed. After 4 weeksstorage at 25 and 40° C., the recovery of all formulations was observedto be between 95-100% of the theoretical concentration and comparable tot=0, with the exception of SS33 which showed a minimal decrease ofbetween 4-5% from 102% to 98 and 97% at 25 and 40° C., respectively. Thepeak purity of all itraconazole formulations after 4 weeks storage at 25and 4° C. were >99.4%, and comparable to the peak purity at t=0.

TABLE 7A Active formulations placed on stability Theoretical composition(%, w/w) SS36-IG2 SS37-IG2 SS38-IG2 SS40-IG2 SS42-IG2 SS43-IG2 SS33-IG22% HPC 2% HPC 2% HPC 2% HPC 2% HPC 2% HPC 2% HPC 0.18% Itr 0.10% Itr0.25% Itr 0.25% Itr 0.55% Itr 0.70% Itr 0.25% Itr Excipient A A A A A AA Phenoxyethanol — 1.00 — — — — — Benzyl alcohol 5.00 — 5.00 5.00 5.005.00 5.00 diethylene 25.00 25.00 25.00 — 25.00 25.00 25.00 glycolmonoethyl ether Ethanol 52.72 56.80 47.65 47.65 27.35 22.20 30.65Propylene — — — — — — 20.00 glycol Solutol — — — — — — 2.00 PEG 400 — —— 25.00 — — — N-methyl-2- — — — — 25.00 25.00 — pyrrolidone Dimethyl15.00 15.00 15.00 15.00 15.00 15.00 15.00 isosorbide Propylene — — 5.005.00 — 5.00 — carbonate Butylated 0.10 0.10 0.10 0.10 0.10 0.10 0.10hydroxytoluene Hydroxypropyl- 2.00 2.00 2.00 2.00 2.00 2.00 2.00cellulose Itraconazole 0.18 0.1 0.25 0.25 0.55 0.7 0.25 (API) Total100.00 100.00 100.00 100.00 100.00 100.00 100.00

TABLE 7B Active Formulations Placed on Stability Theoretical composition(%, w/w) SS44-IG2 SS45-IG2 SS46-IG2 SS47-IG2 SS48-IG2 SS49-IG2 SS50-IG22% HPC 2% HPC 2% HPC 2% HPC 2% HPC 2% HPC 2% HPC 0.18% Itr 0.10% Itr0.50% Itr 0.50% Itr 0.18% Itr 0.20% Itr 0.25% Itr Excipient A A A A A AA Phenoxyethanol — — 1.00 — — — — Benzyl alcohol 5.00 5.00 — 5.00 5.005.00 5.00 diethylene 25.00 25.00 25.00 25.00 25.00 25.00 25.00 glycolmonoethyl ether Ethanol 52.72 52.80 31.40 22.40 22.72 — — Propylene — —— — 20.00 19.80 19.75 glycol Glycerol — — — — 10.00 10.00 10.00 PEG 400— 15.00 — 15.00 — 22.90 17.90 N-methyl-2- — — 25.00 25.00 — — —pyrrolidone Dimethyl 15.00 — 15.00 — 15.00 15.00 15.00 isosorbidePropylene — — — 5.00 — — 5.00 carbonate Butylated — 0.10 0.10 0.10 0.100.10 0.10 hydroxytoluene Hydroxypropyl- 2.00 2.00 2.00 2.00 2.00 2.002.00 cellulose Itraconazole 0.18 0.1 0.5 0.5 0.18 0.2 0.25 (API) Total100.00 100.00 100.00 100.00 100.00 100.00 100.00

Formulations selected for additional permeation/penetration experimentsinclude SS37-IG2, SS38-IG2, SS-40-IG2, SS-43-IG2 and SS-50-IG2, based onsolubility of itraconazole, solvent compatibility, apparent pH, and drugstability.

Example 9 Permeation/Penetration of Topical Formulations of Itraconazole

A permeation/skin penetration study was conducted based on formulationsSS37-IG2, SS38-IG2, SS-40-IG2, SS-43-G2 and SS-50-G2, with sampling timepoints t=0, 14, 18, 24, 26, 36, 40, 44, and 48 hours following the sameprotocol as described in Example 1.

Components of each representative topical formulation are describedbelow.

TABLE 8-01 Topical Formulation SS37-IG2 Component w/w % ethanol 56.80w/w ratio EtOH + diethylene glycol monoethyl 25.00 phenoxyethanol/DEGMEEether 2.3 Dimethyl isosorbide 15.00 w/w ratio DEGMEE/DMI 1.7phenoxyethanol 1.00 hydroxypropyl cellulose 2.00 Butylatedhydroxytoluene 0.10 itraconazole 0.10

TABLE 8-02 Topical Formulation SS38-IG2 Component w/w % ethanol 47.65w/w ratio EtOH + diethylene glycol monoethyl ether 25.00 benzylalcohol/DEGMEE 2.11 Dimethyl isosorbide 15.00 w/w ratio DEGMEE/DMI 1.7Benzyl alcohol 5.00 Propylene carbonate 5.00 hydroxypropyl cellulose2.00 Butylated hydroxytoluene 0.10 itraconazole 0.25

TABLE 8-03 Topical Formulation SS40-1G2 Component w/w % ethanol 47.65w/w ratio PEG-400 25.00 EtOH + benzyl alcohol/PEG-400 2.11 Dimethylisosorbide 15.00 w/w ratio PEG/DMI 1.7 Benzyl alcohol 5.00 Propylenecarbonate 5.00 hydroxypropyl cellulose 2.00 Butylated hydroxytoluene0.10 itraconazole 0.25

TABLE 8-04 Topical Formulation SS43-IG2 Component w/w % diethyleneglycol monoethyl ether 25.00 N-methyl pyrrolidone 25.00 ethanol 22.20w/w ratio EtOH + benzyl alcohol/DEGMEE 1.1 Dimethyl isosorbide 15.00 w/wratio DEGMEE/DMI 1.7 Benzyl alcohol 5.00 Propylene carbonate 5.00hydroxypropyl cellulose 2.00 Butylated hydroxytoluene 0.10 itraconazole0.70

TABLE 8-05 Topical Formulation SS50-IG2 Component w/w % diethyleneglycol monoethyl ether 25.00 w/w ratio ternary Propylene glycol 19.75solvent system PPG, PEG, glycerol + benzyl alcohol/DEGMEE 2.12 PEG-40017.90 Dimethyl isosorbide 15.00 w/w ratio DEGMEE/DMI 1.7 Glycerol 10.00Propylene carbonate 5.00 Benzyl alcohol 5.00 hydroxypropyl cellulose2.00 Butylated hydroxytoluene 0.10 itraconazole 0.25

FIG. 4 and FIG. 5 illustrate the results obtained from the full scalepermeation and penetration experiments of itraconazole, respectively.The data generated in the penetration experiment was utilized todetermine the concentration achieved in the Stratum corneum, epidermisand dermis summarized in Table 9. Given that the half maximal inhibitoryconcentration (IC50) for itraconazole is 0.8 μM, the tissueconcentration of itraconazole is adequate to achieve a cellularresponse.

TABLE 9 Summary of concentration of itraconazole in each of the skinmatrices (Stratum corneum, epidermis, dermis) (μM) after the final timepoint (48 h). Concentration of Concentration of Concentrationitraconazole (μM) in itraconazole (μM) of itraconazole FormulationStratum corneum. in epidermis. (μM) in dermis SS37-IG2 1819.6436 39.0019 10.3957 (Test Item 1) SS38-IG2 2086.3566 100.7848 11.9649 (TestItem 2) SS40-IG2 1151.2386  14.8867  6.7681 (Test Item 3) SS43-IG24660.0911 118.9332 34.8528 (Test Item 4) SS50-IG2 2122.1240  49.432718.6353 (Test Item 5)

FIG. 4 provides the cumulative amount of itraconazole permeated throughhuman skin over a 48 hour time period for each of the test items.Formulations demonstrating the highest cumulative amount of itraconazolepermeation were formulations SS50-IG2 and SS-43-IG2; these formulationsexhibited the highest cumulative amount of itraconazole permeation ateach of the time points evaluated, with SS-50 IG2 demonstrating thegreatest overall skin permeation of itraconazole at each of the timepoints evaluated.

FIG. 5 provides information regarding recovery of itraconazole from eachof the skin matrices (stratum corneum, epidermis, dermis) and receiverfluid, in nanograms, following the final 48 hour time point. SS-43-IG2exhibited superior penetration into the stratum corneum, with notablelevels of drug in both the epidermis and dermis as well.

Based upon a consideration of numerous factors including solubility ofitraconazole, solvent system compatibility, apparent pH, formulationstability, and in-vitro skin permeation, representative preferredformulations include SS43-IG2, SS50-IG2 and SS38-IG2.

Example 10 Preparation of an Illustrative Itraconazole Topical GelFormulation

A non-aqueous topical formulation of itraconazole was prepared asfollows. Dehydrated ethanol was added to the formulation vessel,followed by addition of butylated hydroxytoluene (BHT) to theformulation vessel until dissolution. To the mixture was addeddiethylene glycol monoethyl ether (Transcutol® P), followed byN-methyl-2-pyrrolidone (Pharmasolve™). Dimethyl isosorbide was thenadded, followed by addition of propylene carbonate, and benzyl alcohol.The mixture was stirred by propeller until uniform. To the uniformmixture was added itraconazole until dissolved. Hydroxypropylcellulosewas then added accompanied by propeller stirring. Once the HPC additionwas complete, the resulting mixture was stirred until the HPC was fullydispersed. The exemplary formulation contains 0.7% w/w itraconazole.

A total single dose full face application of approximately 125 mg of gelcorresponds to approximately 0.7 mg of itraconazole.

TABLE 10 Quantity per Formula 30 g Tube Material Supplier Grade (% w/w)Fill (g) Itraconazole Letco Medical USP  0.7 0.21 Decatur, AL DehydratedSpectrum USP 22.2 6.66 alcohol New Brunswick, NJ Butylated Spectrum NF 0.1 0.03 hydroxytoluene New Brunswick, NJ Diethylene glycol GattefosseNF 25.0 7.50 monoethyl ether Paramus, NJ (Transcutol P) N-methyl-2-Ashland JP 25.0 7.50 pyrrolidone Wilmington, DE (Pharmasolve) DimethylCroda ≥98.0% isosorbide Edison, NJ 15.0 4.50 (Arlasolve DMI-LQ)Propylene Penta NF  5.0 1.50 carbonate Fairfield, NJ Benzyl alcoholSpectrum NF  5.0 1.50 New Brunswick, NJ Hydroxylpropyl- Ashlandcellulose, (Klucel HF Pharm) Wilmington, DE NF  2.0 0.60

Example 11 In Vivo Administration of Patidegib Via Topical Delivery

A study was conducted to determine the toxicokinetics of patidegib andits metabolite, IPI-230, when patidegib was administered twice daily(approximately 8 hours apart) to Gottingen Minipigs® via dermalapplication for 13 weeks.

The formulation identified herein as SS14 was prepared, with 2%patidegib and with 4% patidegib. A placebo formulation was also preparedthat was identical in all respects to SS14 except for the absence of thepatidegib. The formulation was applied topically to the animals atpatidegib dose levels of 0 mg/kg/day (untreated), 0 mg/kg/day (placebo),40 mg/kg/day, and 80 mg/kg/day to Groups 1, 2, 3, and 4, respectively.Groups 1 and 3 consisted of four animals/sex/group and Groups 2 and 4consisted of six animals/sex/group. Doses were administered twice daily(approximately 8 hours apart). Blood samples were collected from allanimals, survival permitting, on Days 1, 14 (Group 4 only), and 90predose and at approximately 2, 4, 6, 8 (just prior to the second dailydose), 10, 12, 14, 16, and 24 hours following the first daily dose.Plasma samples were assayed for patidegib and IPI-230. Only the 2-hoursamples from the untreated and placebo groups were analyzed.

No. of Animals Approximate Dose Patidegib Group Male Female(mg/kg/day)^(a) 1 (Untreated) 4 4 0 2 (Placebo) 6 6 0 3 (2% Patidegib) 44 40 4 (4% Patidegib) 6 6 80 ^(a)Dose levels calculated assuming a testarticle density of 1 g/mL at an application rate of 2 mL/kg/day (1mL/kg/dose) and based on an average body weight of 14 kg.

Noncompartmental analysis was applied to the individual plasma patidegiband IPI-230 concentration data for males and females. The followingparameters were estimated: C_(max)—Maximum observed concentration;T_(max)—Time of maximum observed concentration; AUC_(Tlast)—Area underthe concentration-time curve from hour 0 to the last measurableconcentration, estimated by the linear trapezoidal rule; AUC₀₋₂₄—Areaunder the concentration-time curve from hour 0 to hour 24, estimated bythe linear trapezoidal rule; DN AUC₀₋₂₄—Dose normalized AUC₀₋₂₄,calculated as AUC₀₋₂₄/dose level; DN C_(max)—Dose normalized C_(max),calculated as C_(max)/dose level. Some of the data is summarized in thetables below.

TABLE 11-1 Summary of the Mean Patidegib C_(max) and AUC₀₋₂₄ inGottingen Minipig ® Plasma Dose Level C_(max) AUC₀₋₂₄ Interval DoseGroup (mg/kg/day) Sex (ng/mL) (ng · hr/mL) Day 1 3 40 F 4.65 56.7 4 80 M3.84 37.7 F 4.03 36.3 MF 3.93 37.1 Day 14 4 80 M 88.7 1390 F 410 6820 MF249 4110 Day 90 3 40 M 8.68 132 F 35.0 526 MF 21.9 329 4 80 M 21.4 352 F141 2310 MF 75.8 1240 Notes: Doses were administered twice dailyapproximately 8 hours apart. Due to limited concentration data above thelower limit of quantitation in males, only females are presented for Day1 at 40 mg/kg/day.

TABLE 11-2 Summary of the Mean IPI-230 C_(max) and AUC₀₋₂₄ in GottingenMinipig ®Plasma Patidegib Dose Level C_(max) AUC₀₋₂₄ Interval Dose Group(mg/kg/day) Sex (ng/mL) (ng · hr/mL) Day 14 4 80 M 1.56^(a) 27.2^(a) F3.47 61.2 MF 3.15 55.5 Day 90 4 80 M 0.567^(a) 3.35* F 1.64 25.5 MF 1.2818.1 Note: Doses were administered twice daily approximately 8 hoursapart. *Value is not a mean (N = 1) and is presented for informationalpurposes only.

The mean concentration-time profiles of patidegib in plasma for the testgroups (male and female results combined) are presented graphically inFIG. 6A and the mean concentration-time profiles of IPI-230 in plasmafor the test groups (male and female results combined) are presentedgraphically in FIG. 6B. The dose normalized C_(max) and AUC₀₋₂₄relationships of patidegib in Gottingen Minipig® plasma are presentedgraphically in for the combined sexes in FIGS. 7A-7B.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

1-23. (canceled)
 24. A composition for intradermal delivery, comprising:patidegib and a solvent system comprising (i) a monohydric primaryalcohol and a polyol in a w/w ratio of between about 0.9-1.8 and (ii) abuffer, wherein patidegib is present in the solvent system between about0.1-10 wt %.
 25. The composition of claim 24, wherein the monohydricprimary alcohol is of the form R—OH, where R is selected from methyl,ethyl, propyl, butyl, and pentyl.
 26. The composition of claim 24,wherein the polyol is selected from propylene glycol, dipropyleneglycol, hexylene glycol, 1,3-butylene glycol, liquid polyethyleneglycols.
 27. The composition of claim 24, wherein the solvent systemfurther comprises diethylene glycol monoethyl ether.
 28. The compositionof claim 27, wherein the composition further comprises a gelling agent.29. The composition of claim 28, wherein the gelling agent ishydroxypropylcellulose.
 30. The composition of claim 29, wherein thecomposition further comprises a preservative.
 31. The composition ofclaim 30, wherein the preservative is phenoxyethanol.
 32. Thecomposition of claim 24, comprising: patidegib and a solvent systemcomprising (i) ethanol and propylene glycol in a w/w ratio of betweenabout 0.9-1.8, (ii) diethylene glycol monoethyl ether, and (iii) abuffer, wherein patidegib is present in the solvent system in an amountbetween about 0.1-10 wt %.
 33. The composition of claim 32, wherein thecomposition further comprises a gelling agent.
 34. The composition ofclaim 33, wherein the gelling agent is hydroxypropylcellulose.
 35. Thecomposition of claim 34, wherein the composition further comprises apreservative.
 36. The composition of claim 35, wherein the preservativeis phenoxyethanol.
 37. The composition of claim 24, wherein thepatidegib has a saturation solubility in the solvent system of betweenabout 2.5-8 wt % and wherein formulation provides an in vitroconcentration of patidegib in the dermis of greater than about 50 μM 48hours after topical application.
 38. A topical delivery system,comprising an intradermal composition according to claim
 24. 39. Thetopical delivery system of claim 38, further comprising a backing memberand membrane joined to define a reservoir in which the composition iscontained.
 40. The topical delivery system of claim 39, wherein themembrane is a non-rate controlling membrane.
 41. A method for treatingbasal cell carcinoma, comprising: topically applying a compositionaccording to claim 1 to a subject in need thereof, whereby saidtopically applying achieves intracutaneous delivery of patidegib in anamount sufficient for treating basal cell carcinoma, with anon-therapeutic concentration of the compound present in the blood ofthe subject.
 42. The method of claim 41, wherein the subject has Gorlinsyndrome.
 43. A method for treating basal cell carcinoma, comprising:topically applying a topical delivery system according to claim 38 to asubject in need thereof, whereby said topically applying achievesintracutaneous delivery of patidegib in an amount sufficient fortreating basal cell carcinoma, with a non-therapeutic concentration ofthe compound present in the blood of the subject.
 44. The method ofclaim 43, wherein the subject has Gorlin syndrome.